Tricyclic compounds

ABSTRACT

The invention provides a compound of Formula (I) 
                         
pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application Ser.No. 61/131,599 filed on Jun. 10, 2008, U.S. Provisional Application Ser.No. 61/131,602 filed on Jun. 10, 2008, U.S. Provisional Application Ser.No. 61/190,159 filed on Aug. 26, 2008 and U.S. Provisional ApplicationSer. No. 61/201,064 filed Dec. 5, 2008, the contents of which areincorporated herein.

BACKGROUND OF THE INVENTION

The invention provides a novel class of compounds, pharmaceuticalcompositions comprising such compounds and methods of using suchcompounds to treat or prevent diseases or disorders associated withabnormal or deregulated kinase activity, particularly diseases ordisorders that involve abnormal activation of the Jak1, Jak2, Jak3,Tyk2, KDR, Flt-3, CDK2, CDK4, TANK, Trk, FAK, Abl, Bcr-Abl, cMet, b-RAF,FGFR3, c-kit, PDGF-R, Syk, PKC kinases or Aurora kinases.

The protein kinases represent a large family of proteins that play acentral role in the regulation of a wide variety of cellular processesand maintenance of cellular function. A partial, non-limiting, list ofthese kinases include: non-receptor tyrosine kinases such as the Januskinase family (Jak1, Jak2, Jak3 and Tyk2); the fusion kinases, such asBCR-Abl, focal adhesion kinase (FAK), Fes, Lck and Syk; receptortyrosine kinases such as platelet-derived growth factor receptor kinase(PDGF-R), the receptor kinase for stem cell factor, c-kit, thehepatocyte growth factor receptor, c-Met, and the fibroblast growthfactor receptor, FGFR3; and serine/threonine kinases such as b-RAF,mitogen-activated protein kinases (e.g., MKK6) and SAPK2β. Aberrantkinase activity has been observed in many disease states includingbenign and malignant proliferative disorders as well as diseasesresulting from inappropriate activation of the immune and nervoussystems. The novel compounds of this invention inhibit the activity ofone or more protein kinases and are, therefore, expected to be useful inthe treatment of kinase-mediated diseases.

SUMMARY OF THE INVENTION

In a first embodiment the invention provides a compound of Formula (I)

pharmaceutically acceptable salts, pro-drugs, biologically activemetabolites, stereoisomers and isomers thereof wherein

T is N, U is N, X is CR³ and Y is N; or

T is CR⁶, U is N, X is CR³ and Y is N; or

T is N, U is CR⁴, X is CR³ and Y is N; or

T is CR⁶, U is CR⁴, X is CR³ and Y is N; or

T is CR⁶, U is N, X is NR³ and Y is C; or

T is O, U is N, X is CR³ and Y is C; or

T is NR⁶, U is N, X is CR³ and Y is C; or

T is CR⁶, U is CR⁴, X is NR³ and Y is C; or

T is S, U is N, X is CR³ and Y is C;

R¹, R² and R⁵ are each independently hydrogen, deuterium,—N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)),—C(O)R^(a), —C(OH)R^(a)R^(b), —N(R^(a))S(O)₂—R^(b),—S(O)₂N(R^(a))(R^(b)), —CF₃, —OCF₃, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₂-C₆)alkenyl, optionally substituted(C₂-C₆)alkynyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted (C₁-C₁₀)heterocyclyl, or optionally substituted (C₆-C₁₀)aryl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or        optionally substituted (C₁-C₁₀)heteroaryl linked through a        nitrogen;

R³ is hydrogen, an optionally substituted bridged (C₅-C₁₂)cycloalkyl,optionally substituted bridged (C₂-C₁₀)heterocyclyl, optionallysubstituted (C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₃-C₈)cycloalkenyl, optionally substituted(C₆-C₁₀)aryl, optionally substituted (C₁-C₁₀)heteroaryl, optionallysubstituted (C₂-C₁₀)heterocyclyl; or

R³ is -A-D-E-G, wherein A is attached to X and:

A is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R³—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)— or—N(R^(a))C(O)N(R^(b))—R^(e)—;

D is an optionally substituted (C₁-C₈)alkylene, optionally substitutedbridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

E is a bond, —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—,—R^(e)—C(O)O—R^(e)—, R^(e)—C(O)C(O)N(R^(a))—R^(e)—,—R^(e)—N(R^(a))—C(O)C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, —R^(e)—C(O)N(R^(a))R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—OC(O)—R^(e), —R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—,—R^(e)—N(R^(a))S(O)₂—R^(e)—, or —R^(e)—S(O)₂N(R^(a))—R^(e)—; or

E is

where in all cases, E is linked to either a carbon or a nitrogen atom inD;

G is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —OC(O)N(R^(a)),—N(R^(a))C(O)N(R^(b))₂, —C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃,—N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), anoptionally substituted —(C₁-C₆)alkyl, an optionally substituted—(C₂-C₆)alkenyl, an optionally substituted —(C₂-C₆)alkynyl, anoptionally substituted —(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₁₀)heteroaryl, an optionally substituted —(C₁-C₁₀) heterocyclyl,an optionally substituted —(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkyl-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkyl-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkyl-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkyl-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R⁴ and R⁶ are each independently a hydrogen, halogen, deuterium, anoptionally substituted bridged (C₅-C₁₂)cycloalkyl group, optionallysubstituted bridged (C₂-C₁₀)heterocyclyl group, optionally substituted(C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionallysubstituted (C₃-C₈)cycloalkenyl, optionally substituted (C₆-C₁₀)aryl,optionally substituted (C₁-C₁₀)heteroaryl, optionally substituted(C₂-C₁₀)heterocyclyl or -J-L-M-Q;

wherein:

J is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—N(R^(a))—R^(e)—, —S—R^(e)—S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—;

L is a bond, an optionally substituted (C₁-C₈)alkylene, optionallysubstituted bridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

M is a bond, —R^(e)—R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—,—R^(e)—C(O)O—R^(e)—, —R^(e)—OC(O)—R^(e)—, —R^(e)—,C(O)C(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))—C(O)C(O)—R^(e)—,—R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—, —R^(e)—S(O)—R^(e)—,—R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)—R^(e)—,—R^(e)—C(O)N(R^(a))R^(e)—, —R^(e)—OC(O)N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)OR^(e)—, —R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—,—R^(e)—N(R^(a))S(O)₂—R^(e)—, or —R^(e)—S(O)₂N(R^(a))—R^(e)—; or

M is

where in all cases, M is linked to either a carbon or a nitrogen atom inL;

Q is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —N(R^(a))C(O)N(R^(b))₂,—C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b),—S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), an optionallysubstituted (C₁-C₆)alkyl, an optionally substituted (C₂-C₆)alkenyl, anoptionally substituted (C₂-C₆)alkynyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted (C₁-C₁₀)heteroaryl, anoptionally substituted (C₁-C₁₀) heterocyclyl, an optionally substituted(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkyl-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkyl-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R^(a) and R^(b) are each independently hydrogen, deuterium, anoptionally substituted (C₁-C₁₀)alkyl, an optionally substituted(C₂-C₁₀)alkenyl, an optionally substituted (C₂-C₁₀)alkynyl, anoptionally substituted (C₁-C₁₀)alkyl-O—(C₁-C₁₀)alkyl, an optionallysubstituted (C₃-C₁₀)cycloalkyl, an optionally substituted (C₆-C₁₀)aryl,an optionally substituted (C₁-C₁₀)heteroaryl, an optionally substituted(C₁-C₁₀)heterocyclyl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl; and

R^(e) for each occurrence is independently a bond, an optionallysubstituted (C₁-C₁₀)alkylene, an optionally substituted(C₂-C₁₀)alkenylene, an optionally substituted (C₂-C₁₀)alkynylene, anoptionally substituted —(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkylene group, anoptionally substituted (C₃-C₁₀)cycloalkylene, an optionally substituted(C₆-C₁₀)arylene, an optionally substituted (C₁-C₁₀)heteroarylene, or anoptionally substituted (C₁-C₁₀)heterocyclylene;

provided that when the compound is

R³ is defined as above and R⁶ is not linked to the pyrazole ring by anitrogen or oxygen atom; and

provided that when the compound is

when R³ is H, CH₃ or —C(O)OH then R⁴ is not H, —C(O)OCH₂CH₃,—C(O)NH-optionally substituted phenyl-NHC(O)-optionally substitutedphenyl or —S(O)₂-phenyl.

In a second embodiment the invention provides a compound of Formula (II)

pharmaceutically acceptable salts, pro-drugs, biologically activemetabolites, stereoisomers and isomers thereof wherein

when T is NR⁶, U is N, X is CR³ and there is a double bond between U andX;

when T is O, U is N, X is CR³ and there is a double bond between U andX;

when T is CR⁶, U is N, X is NR³ and there is a double bond between T andU;

when T is CR⁶, U is CR⁴, X is NR³ and there is a double bond between Tand U;

R¹, R² and R⁵ are independently hydrogen, deuterium, —N(R^(a))(R^(b)),halogen, —OR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a),—CN, —C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)), —C(O)R^(a) ,—N(R^(a))S(O)₂—, —S(O)₂N(R^(a))—, —CF₃, —OCF₃, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl, optionallysubstituted (C₂-C₆)alkynyl, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₁-C₁₀)heteroaryl, optionally substituted(C₁-C₁₀) heterocyclyl, or optionally substituted (C₆-C₁₀)aryl;

wherein in a moiety comprising —N(R^(a))(R^(b)), the nitrogen, R^(a) andR^(b) may form a ring such that —N(R^(a))(R^(b)) represents anoptionally substituted (C₂-C₁₀)heterocyclyl linked through a nitrogen;

R³ is an optionally substituted bridged (C₅-C₁₂)cycloalkyl group,optionally substituted bridged (C₂-C₁₀)heterocyclyl group, optionallysubstituted adamantyl, optionally substituted (C₁-C₈)alkyl, optionallysubstituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₈)cycloalkenyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted(C₂-C₁₀)heterocyclyl or -A-D-E-G;

wherein:

A is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —C(O—R^(a))(R^(b))—R^(e)—,—S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)— or—N(R^(a))C(O)N(R^(b))—R^(e)—;

D is an optionally substituted (C₁-C₈)alkylene, optionally substitutedbridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted (C₆-C₁₀)arylene,optionally substituted (C₁-C₁₀)heteroarylene, optionally substitutedbridged (C₂-C₁₀)heterocyclylene or optionally substituted(C₂-C₁₀)heterocyclylene;

E is a bond, —R^(e)—, —C(O)—R^(e)—, —C(O)C(O)—R^(e)—, —C(O)O—R^(e)—,—C(O)C(O)N(R^(a))—R^(e)— O—R^(e)—, —S(O)₂—R^(e)—, —S(O)—R^(e)—,—S—R^(e)—, —N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—, —C(O)N(R^(a))—R^(e)—,—OC(O)N(R^(a))—R^(e)—, —OC(O)—R^(e)—, —N(R^(a))C(O)N(R^(b))—R^(e)—,—N(R^(a))S(O)₂—R^(e) or —S(O)₂N(R^(a))—R^(e)—; or

E is

where in all cases, E is linked to either a carbon or a nitrogen atom inD;

G is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), N(R^(a))C(O)OR^(b), —N(R^(a))C(O)N(R^(b))₂,—C(O—R^(a))(R^(b))₂, C(O)R^(a), —CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b),—S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), an optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, optionally substituted(C₃-C₁₀)cycloalkyl, optionally substituted (C₁-C₁₀)heteroaryl,optionally substituted (C₁-C₁₀)heterocyclyl, optionally substituted(C₆-C₁₀)aryl, optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, optionally substituted—(C₁-C₆)alkyl-(C₆-C₁₀)aryl, optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl or optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety comprising —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl linked        through a nitrogen;

R⁶ is a hydrogen, deuterium, an optionally substituted bridged(C₃-C₁₂)cycloalkyl group, optionally substituted bridged(C₂-C₁₀)heterocyclyl group, optionally substituted adamantyl, optionallysubstituted (C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₃-C₈)cycloalkenyl, optionally substituted(C₆-C₁₀)aryl, optionally substituted (C₁-C₁₀)heteroaryl or optionallysubstituted (C₂-C₁₀)heterocyclyl; or R⁶ is -J-L-M-Q, wherein:

J is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —C(O—R^(a))(R^(b))—R^(e)—,or —S(O)₂N(R^(a))R^(e)—;

L is a bond, an optionally substituted (C₁-C₈)alkylene, optionallysubstituted bridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted (C₆-C₁₀)arylene,optionally substituted (C₁-C₁₀)heteroarylene, optionally substitutedbridged (C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene; or

L is

M is a bond, —R^(e)—, —C(O)—R^(e)—, —C(O)C(O)—R^(e)—, —C(O)O—R^(e)—,—C(O)C(O)N(R^(a))—R^(e)—, —O—R^(e)—, —S(O)₂—R^(e)—, —S(O)—R^(e)—,—S—R^(e)—, —N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—, —C(O)N(R^(a))—R^(e)—,—OC(O)N(R^(a))—R^(e)—, —OC(O)—R^(e)—, —N(R^(a))C(O)N(R^(b))—R^(e)—,—N(R^(a))S(O)₂—R^(e) or —S(O)₂N(R^(a))—R^(e)—;

Q is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(e)—,—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —N(R^(a))C(O)N(R^(b))₂,—C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b),—S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), optionally substituted(C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl, optionallysubstituted (C₂-C₆)alkynyl, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₁-C₁₀)heteroaryl, optionally substituted(C₁-C₁₀)heterocyclyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted —(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, optionally substituted—(C₁-C₆)alkyl-(C₁-C₁₀)heteroaryl or optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety comprising —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl linked        through a nitrogen;

R⁴ is hydrogen, deuterium, optionally substituted bridged (C₃-C₁₂)cycloalkyl group, optionally substituted bridged (C₂-C₁₀)heterocyclylgroup, optionally substituted adamantyl, optionally substituted(C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionallysubstituted (C₃-C₈)cycloalkenyl, optionally substituted (C₆-C₁₀)aryl,optionally substituted (C₁-C₁₀)heteroaryl or optionally substituted(C₂-C₁₀)heterocyclyl; or

R⁴ is —V—W—Y-Z wherein:

V is a bond, —C(O)—, optionally substituted (C₁-C₆)alkyl, optionallysubstituted (C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl,optionally substituted (C₃-C₁₂)cycloalkyl, optionally substituted(C₂-C₆)heterocyclyl, —C(O)N(R^(a))—R^(e)—, —C(O—R^(a))(R^(b))—R^(e)—, or—S(O)₂N(R^(a))R^(e)—;

W is a bond, an optionally substituted (C₁-C₈)alkyl, optionallysubstituted bridged (C₅-C₁₂)cycloalkyl, optionally substituted(C₃-C₁₀)cycloalkyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted bridged(C₂-C₁₀)heterocyclyl or an optionally substituted (C₂-C₁₀)heterocyclyl;or

W is

Y is a bond, —R^(e)—, —C(O)—R^(e)—, —C(O)C(O)—R^(e)—, —C(O)O—R^(e)—,—C(O)C(O)N(R^(a))—R^(e)—O—R^(e)—, —S(O)₂—R^(e)—, —S(O)—R^(e)—,—S—R^(e)—, —N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—, —C(O)N(R^(a))—R^(e)—,—OC(O)N(R^(a))—R^(e)—, —OC(O)—R^(e)—, —N(R^(a))C(O)N(R^(b))—R^(e)—,—N(R^(a))S(O)₂—R^(e) or —S(O)₂N(R^(a))—R^(e)—;

Z is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(b), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —N(R^(a))C(O)N(R^(b))₂,—C(O—R^(a))(R^(b))₂, —C(O)R^(b), —CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b),—S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), an optionallysubstituted (C₁-C₆)alkyl, an optionally substituted (C₂-C₆)alkenyl, anoptionally substituted (C₂-C₆)alkynyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted (C₁-C₁₀)heteroaryl, anoptionally substituted (C₁-C₁₀)heterocyclyl, an optionally substituted(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkyl-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

wherein in a moiety comprising —N(R^(a))(R^(b)), the nitrogen, R^(a) andR^(b) may form a ring such that —N(R^(a))(R^(b)) represents anoptionally substituted (C₂-C₁₀)heterocyclyl linked through a nitrogen;

R^(a) and R^(b) are independently hydrogen, deuterium, optionallysubstituted (C₁-C₁₀)alkyl, optionally substituted (C₂-C₁₀)alkenyl,optionally substituted (C₂-C₁₀)alkynyl, optionally substituted—(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkyl, optionally substituted(C₃-C₁₀)cycloalkyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted(C₁-C₁₀)heterocyclyl, optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl or optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl; and

R^(e) is a bond or is independently selected from optionally substituted(C₁-C₁₀)alkylene, optionally substituted (C₂-C₁₀)alkenylene, optionallysubstituted (C₂-C₁₀)alkynylene, optionally substituted—(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkylene-group, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted (C₆-C₁₀)arylene,optionally substituted (C₁-C₁₀)heteroarylene, or optionally substituted(C₁-C₁₀)heterocyclylene;

provided that when the compound is

R⁶ is not linked to the pyrazole ring by a nitrogen or oxygen atom; and

provided the compound is not

wherein when R³ is H, CH₃ or —C(O)OH and R⁴ is not H, —C(O)OCH₂CH₃,—C(O)NH-optionally substituted phenyl-NHC(O)-optionally substitutedphenyl or —S(O)₂-phenyl.

In a third embodiment the invention provides a compound of formula (Ig)

pharmaceutically acceptable salts, pro-drugs, biologically activemetabolites, stereoisomers and isomers thereof wherein

R¹, R² and R⁵ are each independently hydrogen, deuterium,—N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)),—C(O)R^(a), —N(R^(a))S(O)₂—, —S(O)₂N(R^(a))—, —CF₃, —OCF₃, optionallysubstituted —(C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted —(C₂-C₆)alkynyl, optionally substituted—(C₃-C₁₀)cycloalkyl, optionally substituted —(C₁-C₁₀)heteroaryl,optionally substituted —(C₁-C₁₀) heterocyclyl, or optionally substituted—(C₆-C₁₀)aryl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl linked        through a nitrogen;

R³ is an optionally substituted bridged (C₅-C₁₂) cycloalkyl group,optionally substituted bridged (C₂-C₁₀) heterocyclyl group, optionallysubstituted adamantyl, optionally substituted (C₁-C₈) alkyl, optionallysubstituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₈)cycloalkenyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl or optionally substituted(C₂-C₁₀)heterocyclyl; or R³ is -A-D-E-G, wherein:

A is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—N(R^(a))—R^(e)—, —S—R^(e)—, —C(O—R^(a))(R^(b))—R^(e)—,—S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)— or—N(R^(a))C(O)N(R^(b))—R^(e)—;

D is an optionally substituted (C₁-C₈)alkylene, optionally substitutedbridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted (C₆-C₁₀)arylene,optionally substituted (C₁-C₁₀)heteroarylene, optionally substitutedbridged (C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

E is a bond, —R^(e)—, —C(O)—R^(e)—, —C(O)C(O)—R^(e)—, —C(O)O—R^(e)—,—C(O)C(O)N(R^(a))—R^(e)—, —O—R^(e)—, —S(O)₂—R^(e)—, —S(O)—R^(e)—,—S—R^(e)—, —N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—, —C(O)N(R^(a))—R^(e)—,—OC(O)N(R^(a))—R^(e)—, —OC(O)—R^(e)—, —N(R^(a))C(O)N(R^(b))—R^(e)—,—N(R^(a))S(O)₂—R^(e)— or —S(O)₂N(R^(a))—R^(e)—,

or E is

where in all cases, E is linked to either a carbon or a nitrogen atom inD;

G is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —N(R^(a))C(O)N(R^(b))₂,—C(O—R^(a))(R^(b))₂, C(O)R^(a), —CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b),—S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), an optionallysubstituted (C₁-C₆)alkyl, an optionally substituted (C₂-C₆)alkenyl, anoptionally substituted (C₂-C₆)alkynyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted (C₁-C₁₀)heteroaryl, anoptionally substituted (C₁-C₁₀) heterocyclyl, an optionally substituted(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl linked        through a nitrogen;

R⁴ is a hydrogen, deuterium, an optionally substituted bridged (C₃-C₁₂)cycloalkyl group, optionally substituted bridged (C₂-C₁₀)heterocyclylgroup, optionally substituted adamantyl, optionally substituted (C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₈)cycloalkenyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl or optionally substituted(C₂-C₁₀)heterocyclyl; or

R⁴ is -J-L-M-Q, wherein:

J is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —C(O—R^(a))(R^(b))—R^(e)—,or —S(O)₂N(R^(a))R^(e)—;

L is a bond or an optionally substituted (C₁-C₈) alkylene, optionallysubstituted bridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted (C₆-C₁₀)arylene,optionally substituted (C₁-C₁₀)heteroarylene, optionally substitutedbridged (C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

or L is

M is a bond, —R^(e)—, —C(O)—R^(e)—, —C(O)C(O)—R^(e)—, —C(O)O—R^(e)—,—C(O)C(O)N(R^(a))—R^(e)—, —O—R^(e)—, —S(O)₂—R^(e)—, —S(O)—R^(e)—,—S—R^(e)—, —N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—, —C(O)N(R^(a))—R^(e)—,—OC(O)N(R^(a))—R^(e)—, —OC(O)—R^(e)—, —N(R^(a))C(O)N(R^(b))—R^(e)—,—N(R^(a))S(O)₂—R^(e)— or —S(O)₂N(R^(a))—R^(e)—;

Q is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —N(R^(a))C(O)N(R^(b))₂,—C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b),—S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), an optionallysubstituted (C₁-C₆)alkyl, an optionally substituted (C₂-C₆)alkenyl, anoptionally substituted (C₂-C₆)alkynyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted (C₁-C₁₀)heteroaryl, anoptionally substituted (C₁-C₁₀)heterocyclyl, an optionally substituted(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl linked        through a nitrogen;

R^(a) and R^(b) are independently hydrogen, deuterium, an optionallysubstituted (C₁-C₁₀)alkyl, an optionally substituted (C₂-C₁₀)alkenyl, anoptionally substituted (C₂-C₁₀)alkynyl, an optionally substituted—(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted (C₆-C₁₀)aryl, anoptionally substituted (C₁-C₁₀)heteroaryl, an optionally substituted(C₁-C₁₀)heterocyclyl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl; and

R^(e) is a bond, an optionally substituted (C₁-C₁₀)alkylene, anoptionally substituted (C₂-C₁₀)alkenylene, an optionally substituted(C₂-C₁₀)alkynylene, an optionally substituted—(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkylene-group, an optionally substituted(C₃-C₁₀)cycloalkylene, an optionally substituted (C₆-C₁₀)arylene, anoptionally substituted (C₁-C₁₀)heteroarylene, or an optionallysubstituted (C₁-C₁₀)heterocyclylene.

In a fourth embodiment the invention provides a compound of Formula(III)

pharmaceutically acceptable salts, pro-drugs, biologically activemetabolites, stereoisomers and isomers thereof wherein

X is CR⁶ or N; Y is CR⁴ or N;

R¹, R² and R⁵ are each independently hydrogen, deuterium,—N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)),—C(O)R^(a), —C(OH)R^(a)R^(b), —N(R^(a))S(O)₂—R^(b)—,—S(O)₂N(R^(a))(R^(b)), —CF₃, —OCF₃, optionally substituted—(C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl, optionallysubstituted (C₂-C₆)alkynyl, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₁-C₁₀)heteroaryl, optionally substituted(C₁-C₁₀) heterocyclyl, or optionally substituted (C₆-C₁₀)aryl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or        optionally substituted (C₁-C₁₀)heteroaryl linked through a        nitrogen;

R³ is an optionally substituted bridged (C₅-C₁₂)cycloalkyl group,optionally substituted bridged (C₂-C₁₀)heterocyclyl group, optionallysubstituted (C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₃-C₈)cycloalkenyl, optionally substituted(C₆-C₁₀)aryl, optionally substituted (C₁-C₁₀)heteroaryl or optionallysubstituted (C₂-C₁₀)heterocyclyl; or R³ is -A-D-E-G, wherein:

A is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)or —N(R^(a))C(O)N(R^(b))—R^(e)—;

D is an optionally substituted (C₁-C₈) alkylene, optionally substitutedbridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

E is a bond, —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—,—R^(e)—C(O)O—R^(e)—, R^(e)—C(O)C(O)N(R^(a))—R^(e)—,R^(e)—N(R^(a))—C(O)C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, —R^(e)—C(O)N(R^(a))R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—N(R^(a))C(O)OR^(e)—, —R^(e)—C(O)OR^(e)—,—R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—, R^(e)—N(R^(a))S(O)₂—R^(e)—, or—R^(e)—S(O)₂N(R^(a))—R^(e)—; or

E is

where in all cases, E is linked to either a carbon or a nitrogen atom inD;

G is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —N(R^(a))C(O)N(R^(b))₂,—C(O—R^(a))(R^(b))₂, C(O)R^(a), —CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b),—S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), an optionallysubstituted (C₂-C₆)alkyl, an optionally substituted (C₂-C₆)alkenyl, anoptionally substituted (C₂-C₆)alkynyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted (C₁-C₁₀)heteroaryl, anoptionally substituted (C₁-C₁₀) heterocyclyl, an optionally substituted(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R⁶ is a hydrogen, deuterium, an optionally substituted bridged(C₅-C₁₂)cycloalkyl group, optionally substituted bridged(C₂-C₁₀)heterocyclyl group, optionally substituted (C₁-C₈)alkyl,optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₈)cycloalkenyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl or optionally substituted(C₂-C₁₀)heterocyclyl; or R⁶ is -J-L-M-Q, wherein:

J is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—;

L is an optionally substituted (C₁-C₈)alkylene, optionally substitutedbridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

M is a bond, —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—,—R^(e)—C(O)O—R^(e)—, —R^(e)—C(O)C(O)N(R^(a))—R^(e)—, R^(e)—N(R^(a))C(O)C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, —R^(e)—C(O)N(R^(a))R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—N(R^(a))C(O)OR^(e)—, —R^(e)—C(O)OR^(e)—,—R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—, R^(e)—N(R^(a))S(O)₂—R^(e)—, or—R^(e)—S(O)₂N(R^(a))—R^(e)—; or

M is

where in all cases, M is linked to either a carbon or a nitrogen atom inL;

Q is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —N(R^(a))C(O)N(R^(b))₂,—C(O—R^(a))(R^(b))₂, C(O)R^(a), —CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b),—S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), an optionallysubstituted (C₂-C₆)alkyl, an optionally substituted (C₂-C₆)alkenyl, anoptionally substituted (C₂-C₆)alkynyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted —(C₁-C₁₀)heteroaryl, anoptionally substituted —(C₁-C₁₀) heterocyclyl, an optionally substituted(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R⁴ is a hydrogen, deuterium, an optionally substituted bridged(C₅-C₁₂)cycloalkyl group, optionally substituted bridged(C₂-C₁₀)heterocyclyl group, optionally substituted (C₁-C₈)alkyl,optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₈)cycloalkenyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl or optionally substituted(C₂-C₁₀)heterocyclyl; or R⁴ is —U—V—W-Z wherein:

U is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R³—, —N(R^(a))S(O)₂—R^(e)— or—N(R^(a))C(O)N(R^(b))—R^(e)—;

V is an optionally substituted (C₁-C₈) alkylene, optionally substitutedbridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

W is a bond, —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—,—R^(e)—C(O)O—R^(e)—, R^(e)—C(O)C(O)N(R^(a))—R^(e)—, R^(e)—N(R^(a))C(O)C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, R^(e)—C(O)N(R^(a))R^(e)—,R^(e)—OC(O)N(R^(a))—R^(e)—, R^(e)—N(R^(a))C(O)OR^(e)—,R^(e)—N(R^(a))C(O)OR^(e)—, —R^(e)—C(O)OR^(e)—,—R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—, or—R^(e)—S(O)₂N(R^(a))—R^(e)—; or

W is

where in all cases, W is linked to either a carbon or a nitrogen atom inV;

Z is independently hydrogen, deuterium, —N(R^(a))(R^(b)), halogen,—OR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN,—C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b),—N(R^(a))C(O)N(R^(b))₂, —C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃,—N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), anoptionally substituted —(C₁-C₆)alkyl, an optionally substituted—(C₂-C₆)alkenyl, an optionally substituted —(C₂-C₆)alkynyl, anoptionally substituted —(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₁₀)heteroaryl, an optionally substituted —(C₁-C₁₀) heterocyclyl,an optionally substituted (C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R^(a) and R^(b) are each independently hydrogen, deuterium, anoptionally substituted —(C₁-C₁₀)alkyl, an optionally substituted—(C₂-C₁₀)alkenyl, an optionally substituted —(C₂-C₁₀)alkynyl, anoptionally substituted —(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkyl, an optionallysubstituted —(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₆-C₁₀)aryl, an optionally substituted —(C₁-C₁₀)heteroaryl, anoptionally substituted —(C₁-C₁₀)heterocyclyl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl; and

R^(e) is each independently a bond, an optionally substituted(C₁-C₁₀)alkylene, an optionally substituted (C₂-C₁₀)alkenylene, anoptionally substituted (C₂-C₁₀)alkynylene, an optionally substituted(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkylene group, an optionally substituted(C₃-C₁₀)cycloalkylene, an optionally substituted (C₆-C₁₀)arylene, anoptionally substituted (C₁-C₁₀)heteroarylene, or an optionallysubstituted (C₁-C₁₀)heterocyclylene.

In a fifth embodiment the invention provides a compound of Formula (Ia)

pharmaceutically acceptable salts, pro-drugs, biologically activemetabolites, stereoisomers and isomers thereof wherein

R¹, R² and R⁵ are each independently hydrogen, deuterium,—N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)),—C(O)R^(a), —N(R^(a))S(O)₂—, —S(O)₂N(R^(a))—, —CF₃, —OCF₃, optionallysubstituted —(C₁-C₆)alkyl, optionally substituted —(C₂-C₆)alkenyl,optionally substituted —(C₂-C₆)alkynyl, optionally substituted—(C₃-C₁₀)cycloalkyl, optionally substituted —(C₁-C₁₀)heteroaryl,optionally substituted —(C₁-C₁₀) heterocyclyl, or optionally substituted—(C₆-C₁₀)aryl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl linked        through a nitrogen;

R³ is an optionally substituted bridged (C₅-C₁₂)cycloalkyl group,optionally substituted bridged (C₂-C₁₀)heterocyclyl group, optionallysubstituted adamantyl, optionally substituted (C₁-C₈)alkyl, optionallysubstituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₈)cycloalkenyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl or optionally substituted(C₂-C₁₀)heterocyclyl; or R³ is -A-D-E-G, wherein:

A is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(X)—N(R^(a))—R^(e)—, —S—R^(X)—C(O—R^(a))(R^(b))—R^(e)—,—S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)— or—N(R^(a))C(O)N(R^(b))—R^(e)—;

D is an optionally substituted (C₁-C₈)alkylene, optionally substitutedbridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted (C₆-C₁₀)arylene,optionally substituted (C₁-C₁₀)heteroarylene, optionally substitutedbridged (C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

E is a bond, —R^(e)—, —C(O)—R^(e)—, —C(O)C(O)—R^(e)—, —C(O)O—R^(e)—,—C(O)C(O)N(R^(a))—R^(e)—, —O—R³—, —S(O)₂—R^(e)—, —S(O)—R^(e), —S—R^(e)—,—N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—, —C(O)N(R^(a))—R^(e)—,—OC(O)N(R^(a))—R^(e)—, —OC(O)—R^(e)—, —N(R^(a))C(O)N(R^(b))—R^(e)—,—N(R^(a))S(O)₂—R^(e)— or —S(O)₂N(R^(a))—R^(e)—; or

E is

where in all cases, E is linked to either a carbon or a nitrogen atom inD;

G is independently hydrogen, deuterium, —N(R^(a))(R^(b)), halogen,—OR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN,—C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b),—N(R^(a))C(O)N(R^(b))₂, —C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃,—N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), anoptionally substituted (C₁-C₆)alkyl, an optionally substituted(C₂-C₆)alkenyl, an optionally substituted (C₂-C₆)alkynyl, an optionallysubstituted (C₃-C₁₀)cycloalkyl, an optionally substituted(C₁-C₁₀)heteroaryl, an optionally substituted (C₁-C₁₀) heterocyclyl, anoptionally substituted (C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl linked        through a nitrogen;

R^(a) and R^(b) are independently hydrogen, deuterium, an optionallysubstituted (C₁-C₁₀)alkyl, an optionally substituted (C₂-C₁₀)alkenyl, anoptionally substituted (C₂-C₁₀)alkynyl, an optionally substituted—(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted (C₆-C₁₀)aryl, anoptionally substituted (C₁-C₁₀)heteroaryl, an optionally substituted(C₁-C₁₀)heterocyclyl, an optionally substituted—(C₁-C₆)alkyl-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl; and

R^(e) is each independently a bond, optionally substituted(C₁-C₁₀)alkylene, an optionally substituted (C₂-C₁₀)alkenylene, anoptionally substituted (C₂-C₁₀)alkynylene, an optionally substituted—(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkyl-group, an optionally substituted(C₃-C₁₀)cycloalkylene, an optionally substituted (C₆-C₁₀)arylene, anoptionally substituted (C₁-C₁₀)heteroarylene, or an optionallysubstituted (C₁-C₁₀)heterocyclylene.

In a sixth embodiment the invention provides a compound according to thefirst embodiment wherein R¹, R² and R⁵ are each independently hydrogen,deuterium, halogen, —OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)(R^(b)), —CF₃, —OCF₃, an optionally substituted—(C₁-C₆)alkyl, optionally substituted —(C₂-C₆)alkynyl, optionallysubstituted —(C₃-C₁₀)cycloalkyl, optionally substituted—(C₁-C₁₀)heteroaryl, —(C₁-C₁₀)heterocyclyl or optionally substituted—(C₆-C₁₀)aryl.

In a seventh embodiment the invention provides a compound according tothe first embodiment wherein T is N, U is N, X is CR³, Y is N and formsa compound of Formula (Ia)

In an eighth embodiment the invention provides a compound according tothe first embodiment wherein T is CR⁶, U is N, X is CR³ and Y is N andforms a compound of Formula (Ib)

In a ninth embodiment the invention provides a compound according to thefirst embodiment wherein T is N, U is CR⁴, X is CR³, and Y is N andforms a compound of Formula (Ic)

In a tenth embodiment the invention provides a compound according to thefirst embodiment wherein T is CR⁶, U is CR⁴, X is CR³ and Y is N andforms a compound of Formula (Id)

In an eleventh embodiment the invention provides a compound according tothe first embodiment wherein T is CR⁶, U is N, X is NR³ and Y is C andforms a compound of Formula (Ie)

In a twelfth embodiment the invention provides a compound according tothe first embodiment wherein T is O, U is N, X is CR³ and Y is C andforms a compound of Formula (If)

In a thirteenth embodiment the invention provides a compound accordingto the first embodiment wherein T is NR⁶, U is N, X is CR³, and Y is Cand forms a compound of Formula (Ig)

In a fourteenth embodiment the invention provides a compound accordingto the first embodiment wherein T is CR⁶, U is CR⁴, X is NR³, and Y is Cand forms a compound of Formula (Ih)

In a fifteenth embodiment the invention provides compound according tothe first embodiment wherein T is S, U is N, X is CR³ and Y is C andforms a compound of Formula (II)

In a sixteenth embodiment the invention provides compound according tothe first embodiment wherein R³ is hydrogen, an optionally substitutedbridged (C₅-C₁₂)cycloalkyl group, optionally substituted bridged(C₂-C₁₀)heterocyclyl group, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₆-C₁₀)aryl, optionally substituted (C₁-C₁₀)heteroaryl or optionallysubstituted (C₂-C₁₀)heterocyclyl.

In a seventeenth embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein R³ is hydrogen, optionallysubstituted cyclopropyl, optionally substituted cyclobutyl, optionallysubstituted cyclopentyl, optionally substituted cyclohexyl, optionallysubstituted phenyl, optionally substituted adamantanyl, optionallysubstituted azetidinyl, optionally substituted bicyclo[2.1.1]hexyl,optionally substituted bicyclo[2.2.1]heptyl, optionally substitutedbicyclo[2.2.2]octyl, optionally substituted bicyclo[3.2.1]octyl,optionally substituted bicyclo[4.3.1]decyl, optionally substitutedbicyclo[3.3.1]nonyl, optionally substituted bornyl, optionallysubstituted bornenyl, optionally substituted norbornyl, optionallysubstituted norbornenyl, optionally substituted bicyclo[3.1.1]heptyl,optionally substituted tricyclobutyl, optionally substitutedazanorbornyl, optionally substituted quinuclidinyl, optionallysubstituted isoquinuclidinyl, optionally substituted tropanyl,optionally substituted azabicyclo[3.2.1]octanyl, optionally substitutedazabicyclo[2.2.1]heptanyl, optionally substituted2-azabicyclo[3.2.1]octanyl, optionally substitutedazabicyclo[3.2.1]octanyl, optionally substitutedazabicyclo[3.2.2]nonanyl, optionally substitutedazabicyclo[3.3.0]nonanyl, optionally substitutedazabicyclo[3.3.1]nonanyl, optionally substitutedbicycle[2.2.1]hept-2-enyl, optionally substituted piperidinyl,optionally substituted pyrrolidinyl or optionally substitutedtetrahydrofuranyl.

In an eighteenth embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein R³ is optionally substitutedcyclopropyl, optionally substituted cyclobutyl, optionally substitutedcyclopentyl, optionally substituted cyclohexyl, optionally substitutedphenyl, optionally substituted adamantanyl, optionally substitutedazetidinyl, optionally substituted bicyclo[2.1.1]hexyl, optionallysubstituted bicyclo[2.2.1]heptyl, optionally substitutedbicyclo[2.2.2]octyl, optionally substituted bicyclo[3.2.1]octyl,optionally substituted bicyclo[3.1.1]heptyl, optionally substitutedazabicyclo[3.2.1]octanyl, optionally substitutedazabicyclo[2.2.1]heptanyl, optionally substituted2-azabicyclo[3.2.1]octanyl, optionally substitutedazabicyclo[3.2.2]nonanyl, optionally substitutedbicyclo[2.2.1]hept-2-enyl, optionally substituted piperidinyl,optionally substituted pyrrolidinyl or optionally substitutedtetrahydrofuranyl.

In a nineteenth embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein R³ is A-D-E-G.

In a twentieth embodiment the invention provides a compound according toany of the foregoing embodiments wherein A is a bond, —C(O)—, optionallysubstituted (C₁-C₆)alkylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—N(R^(a))—R^(e)—, —C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—,—N(R^(a))S(O)₂—R^(e)— or —N(R^(a))C(O)N(R^(b))—R^(e).

In a twenty-first embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein D is optionally substitutedazetidinyl, optionally substituted bridged (C₅-C₁₂)cycloalkylene,optionally substituted (C₃-C₁₀)cycloalkylene, optionally substitutedbridged (C₅-C₁₀)cycloalkenylene, optionally substituted(C₅-C₁₀)cycloalkenylene, optionally substituted (C₆-C₁₀)arylene,optionally substituted (C₁-C₁₀)heteroarylene, optionally substitutedbridged (C₂-C₁₀)heterocyclylene, or an optionally substituted(C₂-C₁₀)heterocyclylene.

In a twenty-second embodiment the invention provides a compoundaccording to any of the foregoing embodiments wherein E is a bond, —R—,—R^(e)—C(O)—R^(e)—, —R^(e)—, —R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)—R^(e)—,—R^(e)—C(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—, —R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—, or —W—S(O)₂N(R^(a))—R^(e)—.

In a twenty-third embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein G is —OR^(a), CN,—N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)), optionally substituted(C₁-C₆)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted(C₁-C₁₀)heterocyclyl or optionally substituted phenyl.

In a twenty-fourth embodiment the invention provides a compoundaccording to any of the foregoing embodiments wherein R³ is A-D-E-G andA is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene,—C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—, —O—, —N(R^(a))—, —S—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—, —N(R^(a))S(O)₂— or—N(R^(a))C(O)N(R^(b))—.

In a twenty-fifth embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein D is an optionallysubstituted azetidinyl, optionally substituted bicyclo[2.2.2]octanylene,optionally substituted bicyclo[2.2.1]heptylene, optionally substitutedbicyclo[2.1.1]hexylene, optionally substituted cyclobutylene, optionallysubstituted cyclopentylene, optionally substituted cyclohexylene,optionally substituted bicyclo[2.2.1]hept-2-enylene, optionallysubstituted piperidine, or optionally substituted pyrrolidine.

In a twenty-sixth embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein E is —R^(e)—C(O)—R^(e)—,R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, —R^(e)—C(O)N(R^(a))R^(e)—,—R^(e)—N(R^(a))S(O)₂—R^(e)—, or —R^(e)—S(O)₂N(R^(a))R^(e)—.

In a twenty-seventh embodiment the invention provides a compoundaccording to any of the foregoing embodiments wherein G is OR^(a), —CN,—N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)), optionally substituted(C₁-C₆)alkyl, optionally substituted cyclopropyl, optionally substitutedcyclobutyl, optionally substituted cyclopentyl, optionally substitutedphenyl, optionally substituted pyridazine, optionally substitutedpyrazine, optionally substituted pyrimidine, optionally substitutedpyrazole, optionally substituted pyrrolidine, optionally substitutedquinazoline, optionally substituted pyridinel, optionally substitutedthiazolidinel or optionally substituted triazole.

In a twenty-eighth embodiment the invention provides a compoundaccording to any of the foregoing embodiments wherein A is a bond oroptionally substituted (C₁-C₆)alkylene.

In a twenty-ninth embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein D is an optionallysubstituted cyclobutylene, optionally substituted cyclopentylene,optionally substituted cyclohexylene, optionally substituted azetidinyl,optionally substituted bicyclo[2.2.1]heptylene, optionally substitutedbicyclo[2.1.1]hexylene, bicyclo[2.2.2]octanylene, optionally substitutedpiperidine, or optionally substituted pyrrolidine;

E is —R^(e)—C(O)—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—N(R^(a))S(O)₂—R^(e)—, —R^(e)—S(O)₂—R^(e)—, or—R^(e)—S(O)₂N(R^(a))—R^(e)—, wherein R^(e) for each occurrence isindependently a bond, an optionally substituted (C₁-C₆)alkylene or anoptionally substituted (C₃-C₆)cycloalkylene; and

G is —CN, optionally substituted (C₁-C₆)alkyl, optionally substitutedcyclopropyl, optionally substituted cyclobutyl, optionally substitutedcyclopentyl, optionally substituted phenyl, optionally substitutedpyrazinyl, optionally substituted pyridazinyl, optionally substitutedpyrimidinyl, optionally substituted pyrazolyl, optionally substitutedpyridinyl, optionally substituted thiazolidinyl or optionallysubstituted triazolyl.

In a thirtieth embodiment the invention provides a compound according toany of the foregoing embodiments wherein D is an optionally substitutedcyclobutylene, optionally substituted cyclopentylene, optionallysubstituted cyclohexylene, optionally substituted azetidinyl, optionallysubstituted piperidine, optionally substituted bicyclo[2.2.1]heptylene,or bicyclo[2.2.2]octanylene.

In a thirty-first embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein G is —CN, optionallysubstituted (C₁-C₆)alkyl, optionally substituted cyclopropyl, optionallysubstituted cyclobutyl, optionally substituted cyclopentyl or optionallysubstituted phenyl, optionally substituted pyrazinyl, optionallysubstituted pyridazinyl, optionally substituted pyrazolyl, or optionallysubstituted pyridinyl.

In a thirty-second embodiment the invention provides a compoundaccording to any of the foregoing embodiments wherein A is a bond, D isoptionally substituted cyclopentylene, optionally substitutedbicyclo[2.2.2]octanyl, optionally substituted azetidinyl, or optionallysubstituted piperidine;

E is —R^(e)—C(O)—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—S(O)₂N(R^(a))—R^(e)—, —R^(e)—S(O)₂—R^(e)— or—R^(e)—N(R^(a))S(O)₂—R^(e)—;

-   -   wherein R^(e) for each occurrence is independently a bond or an        optionally substituted (C₁-C₆)alkylene; and

G is —CN, optionally substituted cyclopropyl, optionally substitutedcyclobutyl, optionally substituted cyclopentyl, optionally substitutedphenyl, optionally substituted pyrazine, optionally substitutedpyridazine, optionally substituted pyrazole, or optionally substitutedpyridine.

In a thirty-third embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein G is —CN, optionallysubstituted cyclopropyl or optionally substituted cyclopentyl.

In a thirty-fourth embodiment the invention provides a compoundaccording to any of the foregoing embodiments wherein R¹, R², R⁴, R⁵ andR⁶ when present are each independently hydrogen or an optionallysubstituted —(C₁-C₄)alkyl.

In a thirty-fifth embodiment the invention provides a compound accordingto the first, second, fourth, fifth, seventh and sixteenth throughthirty-third embodiments wherein the compound is a compound of Formula(Ia)

In a thirty-sixth embodiment the invention provides a compound accordingto the first, fourth, eighth, and sixteenth through thirty-thirdembodiments wherein the compound is a compound of Formula (Ib)

In a thirty-seventh embodiment the invention provides a compoundaccording to the first, fourth, ninth and sixteenth through thirty-thirdembodiments wherein the compound is a compound of Formula (Ic)

In a thirty-eighth embodiment the invention provides a compoundaccording to any of the foregoing embodiments wherein T is N, U is N, Xis CR³ and Y is N.

In a thirty-ninth embodiment the invention provides a compound accordingto the first, fourth, fifth and sixteenth through thirty-thirdembodiments wherein the compound is

In a fortieth embodiment the invention provides a compound according tothe first, fourth, fifth and sixteenth through thirty-third embodimentswherein the compound is

In a forty-first embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein the compound is

In a forty-second embodiment the invention provides a compound accordingto the first through fortieth embodiments wherein A is a bond, D isoptionally substituted cyclopentylene or optionally substitutedpiperidine, E is —R^(e)—N(R^(a))—R^(e)—, —R^(e)—S(O)₂ N(R^(a))—R^(e)—,—R^(e)—C(O)—R^(e)—, —R^(e)— S(O)₂—R^(e)—, or—R^(e)—N(R^(a))S(O)₂—R^(e)—; and G is —CN, optionally substitutedphenyl, optionally substituted pyrazine, optionally substitutedpyridazine, optionally substituted pyrazole, or optionally substitutedpyridine.

In a forty-third embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein T is CR⁶.

In a forty-fourth embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein U is N.

In a forty-fifth embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein X is CR³.

In a forty-sixth embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein Y is N.

In a forty-seventh embodiment the invention provides a compoundaccording to any of the foregoing embodiments wherein T is CR⁶, U is N,X is CR³ and Y is N.

In a forty-eighth embodiment the invention provides a compound accordingto the first, fourth, eighth, sixteenth through thirty-third,thirty-sixth and forty-second through forty-seventh embodiments whereinthe compound is

In a forty-ninth embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein G is optionally substitutedphenyl, optionally substituted pyrazine, optionally substitutedpyrazole, optionally substituted pyridazine or optionally substitutedpyridine.

In a fiftieth embodiment the invention provides a compound according tothe first through sixteenth embodiments wherein R² and R⁵ are eachindependently hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN,—C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)), —C(O)R^(a),—C(OH)R^(a)R^(b), —N(R^(a))S(O)₂—R^(b), —S(O)₂N(R^(a))(R^(b)), —CF₃,—OCF₃, optionally substituted —(C₁-C₆)alkyl, optionally substituted—(C₃-C₆)cycloalkyl, optionally substituted benzo(b)thienyl, optionallysubstituted benzimidazole, optionally substituted benzofuran, optionallysubstituted benzoxazole, optionally substituted benzothiazole,optionally substituted benzothiadiazole, optionally substituted furan,optionally substituted imidazole, optionally substituted indoline,optionally substituted indole, optionally substituted indazole,optionally substituted isoxazole, optionally substituted isoindoline,optionally substituted morpholine, optionally substituted oxadiazole,optionally substituted phenyl, optionally substituted piperazine,optionally substituted piperidine, optionally substituted pyran,optionally substituted pyrazole, optionally substitutedpyrazolo[3,4-d]pyrimidine, optionally substituted pyridine, optionallysubstituted pyrimidine, optionally substituted pyrrolidinel, optionallysubstituted pyrrole, optionally substituted optionallypyrrolo[2,3-d]pyrimidine, substituted quinoline, optionally substitutedthiomorpholine, optionally substituted tetrahydropyran, optionallysubstituted tetrahydrofuran, optionally substituted tetrahydroindol,optionally substituted thiazole, or optionally substituted thienyl.

In a fifty-first embodiment the invention provides a compound accordingto the first through sixteenth and forty-seventh embodiments wherein R¹is optionally substituted (C₆-C₁₀)aryl or optionally substituted(C₁-C₁₀)heteroaryl.

In a fifty-second embodiment the invention provides a compound accordingto the first through sixteenth, forty-seventh and fiftieth embodimentswherein R² is hydrogen, halogen, —CN, —C(O)NR^(a)R^(b), —CF₃, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₃-C₁₂)cycloalkyl,optionally substituted (C₆-C₁₀)aryl, optionally substituted(C₁-C₁₀)heteroaryl or optionally substituted (C₁-C₁₀)heterocyclyl.

In a fifty-third embodiment the invention provides a compound accordingto the first through fifteenth, forty-seventh and forty-ninthembodiments wherein R¹ is optionally substituted azaindole, optionallysubstituted benzofuran, optionally substituted benzothiazole, optionallysubstituted benzoxazole, optionally substituted dihydropyrroloimidazole,optionally substituted furan, optionally substituted imidazole,optionally substituted imidazoxazole, optionally substitutedimidazopyrazine, optionally substituted imidazopyridine, optionallysubstituted indazole, optionally substituted indole, optionallysubstituted isoquinoline, optionally substituted isothiazole, optionallysubstituted isoxazole, optionally substituted oxadiazole, optionallysubstituted oxazole, optionally substituted pyrazole, optionallysubstituted pyridine, optionally substituted pyrimidine, optionallysubstituted pyrazolopyridine, optionally substituted pyrrole, optionallysubstituted quinoline, optionally substituted quinazoline, optionallysubstituted thiazole, or optionally substituted thiophene.

In a fifty-fourth embodiment the invention provides a compound accordingto the first through fifteenth and forty-seventh through fifty-secondembodiments wherein R⁵ is hydrogen, halogen, NH₂ or N(R^(a))(R^(b)).

In a fifty-fifth embodiment the invention provides a compound accordingto the first through fifteenth and forty-seventh through fifty-thirdembodiments wherein T is CH, U is N, Y is N, and X is CR³ wherein R³ is(C₁-C₆)optionally substituted alkyl, (C₃-C₁₂)optionally substitutedcycloalkyl, optionally substituted (C₆-C₁₀)aryl, optionally substituted(C₁-C₁₀)heteroaryl, or optionally substituted (C₁-C₁₀)heterocyclyl.

In a fifty-sixth embodiment the invention provides a compound accordingto the first through fifteenth and forty-seventh through fifty-fourthembodiments wherein R³ is optionally substituted pyrrolidine, optionallysubstituted piperidine, optionally substituted piperazine, optionallysubstituted azetidine, optionally substituted (C₆-C₁₀)aryl, oroptionally substituted (C₁-C₁₀)heterocyclyl.

In a fifty-seventh embodiment the invention provides a compoundaccording to the first through fifteenth and forty-seventh throughfifty-fourth embodiments wherein T is CH, U is N, Y is C and X is NR³wherein R³ is (C₁-C₆)optionally substituted alkyl, (C₃-C₁₀)optionallysubstituted cycloalkyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstitute (C₁-C₁₀)heteroaryl, or optionally substituted(C₁-C₁₀)heterocyclyl.

In a fifty-eighth embodiment the invention provides a compound accordingto the first through fifteenth and forty-eighth through fifty-seventhembodiments wherein R³ is optionally substituted pyrrolidine, optionallysubstituted piperidine, optionally substituted piperazine, optionallysubstituted azetidine, optionally substituted (C₆-C₁₀)aryl, oroptionally substituted (C₁-C₁₀)heterocyclyl.

In a fifty-ninth embodiment the invention provides a compound accordingto the first through fifteenth and forty-eighth through fifty-eighthembodiments wherein T is N, U is N, Y is N and X is CR³ wherein R³ is(C₁-C₆)optionally substituted alkyl, (C₃-C₁₂)optionally substitutedcycloalkyl, optionally substituted (C₆-C₁₀)aryl, optionally substituted(C₁-C₁₀)heteroaryl, or optionally substituted (C₁-C₁₀)heterocyclyl.

In a sixtieth embodiment the invention provides a compound according tothe first through fifteenth and forty-eighth through fifty-ninthembodiments wherein R³ is optionally substituted pyrrolidine, optionallysubstituted piperidine, optionally substituted piperazine, optionallysubstituted azetidine, optionally substituted (C₆-C₁₀)aryl, oroptionally substituted (C₁-C₁₀)heterocyclyl.

In a sixty-first embodiment the invention provides the use of a compoundof Formula 2:

to form a compound of Formula (Ia)

pharmaceutically acceptable salts, pro-drugs, biologically activemetabolites, stereoisomers and isomers thereof wherein

R^(p) is a hydrogen, —SO₂N(CH₃)₂, —SO₂(2,4,6-trimethylphenyl),—SO₂-phenyl, —SO₂(4-butylphenyl), —SO₂(4-methylphenyl),—SO₂(4-methoxyphenyl), —C(O)OCH₂CCl₃, —C(O)OCH₂CH₂Si(CH₃)₃,—C(O)OC(CH₃)₃, —C(O)OC(CH₃)₂(CCl₃), —C(O)O-1-adamantyl, —CH═CH₂,—CH₂CH₂Cl, —CH(OCH₂CH₃)CH₃, —CH₂CH₂-2-pyridyl, —CH₂CH₂-4-pyridyl,—Si(C(CH₃)₃)(CH₃)₂, —Si(CH(CH₃)₂)₃, —CH₂-phenyl, —CH₂(4-CH₃O-phenyl),—CH₂(3,4-dimethoxyphenyl), —CH₂(2-nitrophenyl), -(2,4-dinitrophenyl),—CH₂C(O)phenyl, —C(phenyl)₃, —CH(phenyl)₂, —C(phenyl)₂(4-pyridyl),—N(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH(OCH₂CH₃)₂, —CH₂OCH₂CH₂Cl,—CH₂OCH₂CH₂Si(CH₃)₃, —CH₂OC(CH₃)₃, —CH₂OC(O)C(CH₃)₃, —CH₂OCH₂-phenyl,-(2-tetrahydropyranyl), —C(O)H, or —P(S)(phenyl)₂;

R¹, R² and R⁵ are each independently hydrogen, deuterium,—N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)),—C(O)R^(a), —C(OH)R^(a)R^(b), —N(R^(a))S(O)₂—R^(b),—S(O)₂N(R^(a))(R^(b)), —CF₃, —OCF₃, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₂-C₆)alkenyl, optionally substituted(C₂-C₆)alkynyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted (C₁-C₁₀)heterocyclyl, or optionally substituted (C₆-C₁₀)aryl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or        optionally substituted (C₁-C₁₀)heteroaryl linked through a        nitrogen;

R³ is hydrogen, an optionally substituted bridged (C₅-C₁₂)cycloalkyl,optionally substituted bridged (C₂-C₁₀)heterocyclyl, optionallysubstituted (C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₃-C₈)cycloalkenyl, optionally substituted(C₆-C₁₀)aryl, optionally substituted (C₁-C₁₀)heteroaryl, optionallysubstituted (C₂-C₁₀)heterocyclyl; or

R³ is -A-D-E-G, wherein:

A is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—;

D is an optionally substituted (C₁-C₈)alkylene, optionally substitutedbridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

E is a bond, —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—,—R^(e)—C(O)O—R^(e)—, R^(e)—C(O)C(O)N(R^(a)) R^(e)—, R^(e)—N(R^(a))C(O)C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, —R^(e)—C(O)N(R^(a))R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—OC(O)—R^(e)—, —R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—,—R^(e)—N(R^(a))S(O)₂—R^(e)—, or —R^(e)—S(O)₂N(R^(a))—R^(e)—; or

E is

where in all cases, E is linked to either a carbon or a nitrogen atom inD;

G is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —OC(O)N(R^(a)),—N(R^(a))C(O)N(R^(b))₂, —C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃,—N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), anoptionally substituted —(C₁-C₆)alkyl, an optionally substituted—(C₂-C₆)alkenyl, an optionally substituted —(C₂-C₆)alkynyl, anoptionally substituted —(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₁₀)heteroaryl, an optionally substituted —(C₁-C₁₀) heterocyclyl,an optionally substituted —(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkyl-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen, R^(a) andR^(b) may form a ring such that —N(R^(a))(R^(b)) represents anoptionally substituted (C₂-C₁₀)heterocyclyl or an optionally substituted(C₁-C₁₀) heteroaryl linked through a nitrogen;

R^(a) and R^(b) are each independently hydrogen, deuterium, anoptionally substituted (C₁-C₁₀)alkyl, an optionally substituted(C₂-C₁₀)alkenyl, an optionally substituted (C₂-C₁₀)alkynyl, anoptionally substituted —(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkyl, an optionallysubstituted (C₃-C₁₀)cycloalkyl, an optionally substituted (C₆-C₁₀)aryl,an optionally substituted (C₁-C₁₀)heteroaryl, an optionally substituted(C₁-C₁₀)heterocyclyl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl; and

R^(e) for each occurrence is independently a bond, an optionallysubstituted (C₁-C₁₀)alkylene, an optionally substituted(C₂-C₁₀)alkenylene, an optionally substituted (C₂-C₁₀)alkynylene, anoptionally substituted —(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkylene group, anoptionally substituted (C₃-C₁₀)cycloalkylene, an optionally substituted(C₆-C₁₀)arylene, an optionally substituted (C₁-C₁₀)heteroarylene, or anoptionally substituted (C₁-C₁₀)heterocyclylene.

In a sixty-second embodiment the invention provides the use of acompound of Formula 3:

to form a compound of Formula (Ib)

pharmaceutically acceptable salts, pro-drugs, biologically activemetabolites, stereoisomers and isomers thereof wherein

R^(p) is a hydrogen, —SO₂N(CH₃)₂, —SO₂(2,4,6-trimethylphenyl),—SO₂-phenyl, —SO₂(4-butylphenyl), —SO₂(4-methylphenyl),—SO₂(4-methoxyphenyl), —C(O)OCH₂CCl₃, —C(O)OCH₂CH₂Si(CH₃)₃,—C(O)OC(CH₃)₃, —C(O)OC(CH₃)₂(CCl₃), —C(O)O-1-adamantyl, —CH═CH₂,—CH₂CH₂Cl, —CH(OCH₂CH₃)CH₃, —CH₂CH₂-2-pyridyl, —CH₂CH₂-4-pyridyl,—Si(C(CH₃)₃)(CH₃)₂, —Si(CH(CH₃)₂)₃, —CH₂-phenyl, —CH₂(4-CH₃O-phenyl),—CH₂(3,4-dimethoxyphenyl), —CH₂(2-nitrophenyl), -(2,4-dinitrophenyl),—CH₂C(O)phenyl, —C(phenyl)₃, —CH(phenyl)₂, —C(phenyl)₂(4-pyridyl),—N(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH(OCH₂CH₃)₂, —CH₂OCH₂CH₂Cl,—CH₂OCH₂CH₂Si(CH₃)₃, —CH₂OC(CH₃)₃, —CH₂OC(O)C(CH₃)₃, —CH₂OCH₂-phenyl,-(2-tetrahydropyranyl), —C(O)H, or —P(S)(phenyl)₂;

R¹, R² and R⁵ are each independently hydrogen, deuterium,—N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)),—C(O)R^(a), —C(OH)R^(a)R^(b), —N(R^(a))S(O)₂—R^(b),—S(O)₂N(R^(a))(R^(b)), —CF₃, —OCF₃, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₂-C₆)alkenyl, optionally substituted(C₂-C₆)alkynyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted (C₁-C₁₀)heterocyclyl, or optionally substituted (C₆-C₁₀)aryl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or        optionally substituted (C₁-C₁₀)heteroaryl linked through a        nitrogen;

R³ is hydrogen, an optionally substituted bridged (C₅-C₁₂)cycloalkyl,optionally substituted bridged (C₂-C₁₀)heterocyclyl, optionallysubstituted (C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₃-C₈)cycloalkenyl, optionally substituted(C₆-C₁₀)aryl, optionally substituted (C₁-C₁₀)heteroaryl, optionallysubstituted (C₂-C₁₀)heterocyclyl; or

R³ is -A-D-E-G, wherein:

A is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—;

D is an optionally substituted (C₁-C₈)alkylene, optionally substitutedbridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

E is a bond, —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—,—R^(e)—C(O)O—R^(e)—, R^(e)—C(O)C(O)N(R^(a)) R^(e)—, R^(e)—N(R^(a))C(O)C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, —R^(e)—C(O)N(R^(a))R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—OC(O)—R^(e)—, —R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—,—R^(e)—N(R^(a))S(O)₂—R^(e)—, or —R^(e)—S(O)₂N(R^(a))—R^(e)—; or

E is

where in all cases, E is linked to either a carbon or a nitrogen atom inD;

G is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b),—OC(O)N(R^(a))—N(R^(a))C(O)N(R^(b))₂, —C(O—R^(a))(R^(b))₂, —C(O)R^(a),—CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)),—S(O)₂N(R^(a))C(O)R^(b), an optionally substituted —(C₁-C₆)alkyl, anoptionally substituted —(C₂-C₆)alkenyl, an optionally substituted—(C₂-C₆)alkynyl, an optionally substituted —(C₃-C₁₀)cycloalkyl, anoptionally substituted —(C₁-C₁₀)heteroaryl, an optionally substituted—(C₁-C₁₀) heterocyclyl, an optionally substituted —(C₆-C₁₀)aryl, anoptionally substituted —(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, anoptionally substituted —(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionallysubstituted —(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionallysubstituted —(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R⁶ is a hydrogen, halogen, deuterium, an optionally substituted bridged(C₅-C₁₂)cycloalkyl group, optionally substituted bridged(C₂-C₁₀)heterocyclyl group, optionally substituted (C₁-C₈)alkyl,optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₈)cycloalkenyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted(C₂-C₁₀)heterocyclyl or -J-L-M-Q;

wherein:

J is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—;

L is a bond, an optionally substituted (C₁-C₈)alkylene, optionallysubstituted bridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

M is a bond, —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—,—R^(e)—C(O)O—R^(e)—, —R^(e)—OC(O)—R^(e)—,—R^(e)—C(O)C(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)C(O)—R^(e)—,—R^(e)—S(O)₂—R^(e)—, —R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—,—R^(e)—N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)—R^(e)—,—R^(e)—C(O)N(R^(a))R^(e)—, —R^(e)—OC(O)N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)OR^(e)—, —R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—,—R^(e)—N(R^(a))S(O)₂—R^(e)—, or —R^(e)—S(O)₂N(R^(a))—R^(e)—; or

M is

where in all cases, M is linked to either a carbon or a nitrogen atom inL;

Q is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —N(R^(a))C(O)N(R^(b))₂,—C(O—R^(a))(R^(b))₂, C(O)R^(a), —CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b),—S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), an optionallysubstituted (C₁-C₆)alkyl, an optionally substituted (C₂-C₆)alkenyl, anoptionally substituted (C₂-C₆)alkynyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted (C₁-C₁₀)heteroaryl, anoptionally substituted (C₁-C₁₀)heterocyclyl, an optionally substituted(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R^(a) and R^(b) are each independently hydrogen, deuterium, anoptionally substituted (C₁-C₁₀)alkyl, an optionally substituted(C₂-C₁₀)alkenyl, an optionally substituted (C₂-C₁₀)alkynyl, anoptionally substituted —(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkyl, an optionallysubstituted (C₃-C₁₀)cycloalkyl, an optionally substituted (C₆-C₁₀)aryl,an optionally substituted (C₁-C₁₀)heteroaryl, an optionally substituted(C₁-C₁₀)heterocyclyl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl; and

R^(e) for each occurrence is independently a bond, an optionallysubstituted (C₁-C₁₀)alkylene, an optionally substituted(C₂-C₁₀)alkenylene, an optionally substituted (C₂-C₁₀)alkynylene, anoptionally substituted —(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkylene group, anoptionally substituted (C₃-C₁₀)cycloalkylene, an optionally substituted(C₆-C₁₀)arylene, an optionally substituted (C₁-C₁₀)heteroarylene, or anoptionally substituted (C₁-C₁₀)heterocyclylene.

In a sixty-third embodiment the invention provides use of a compound ofFormula 4:

to form a compound of Formula (Ic)

or pharmaceutically acceptable salts, pro-drugs, biologically activemetabolites, stereoisomers and isomers thereof wherein

R^(p1) is hydrogen, —SO₂N(CH₃)₂, —SO₂(2,4,6-trimethylphenyl),—SO₂-phenyl, —SO₂(4-butylphenyl), —SO₂(4-methylphenyl),—SO₂(4-methoxyphenyl), —C(O)OCH₂CCl₃, —C(O)OCH₂CH₂Si(CH₃)₃,—C(O)OC(CH₃)₃, —C(O)OC(CH₃)₂(CCl₃), —C(O)O-1-adamantyl, —CH═CH₂,—CH₂CH₂Cl, —CH(OCH₂CH₃)CH₃, —CH₂CH₂-2-pyridyl, —CH₂CH₂-4-pyridyl,—Si(C(CH₃)₃)(CH₃)₂, —Si(CH(CH₃)₂)₃, —CH₂-phenyl, —CH₂(4-CH₃O-phenyl),—CH₂(3,4dimethoxyphenyl), —CH₂(2-nitrophenyl), -(2,4-dinitrophenyl),—CH₂C(O)phenyl, —C(phenyl)₃, —CH(phenyl)₂, —C(phenyl)₂(4-pyridyl),—N(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH(OCH₂CH₃)₂, —CH₂OCH₂CH₂Cl,—CH₂OCH₂CH₂Si(CH₃)₃, —CH₂OC(CH₃)₃, —CH₂OC(O)C(CH₃)₃, —CH₂OCH₂-phenyl,-(2-tetrahydropyranyl), —C(O)H, or —P(S)(phenyl)₂;

R^(p2) is hydrogen, —C(O)O—C(CH₃)₃, —C(O)OCH₂-phenyl,—C(O)O-fluoren-9-yl, —C(O)CH₃, —C(O)CF₃, —C(O)—CH(CH₃)₂, —CH₂-phenyl,—CH₂-(4-methoxyphenyl), —S(O)₂-phenyl or —S(O)₂-(4-methylphenyl);

R¹, R² and R⁵ are each independently hydrogen, deuterium,—N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)),—C(O)R^(a), —C(OH)R^(a)R^(b), —N(R^(a))S(O)₂—R^(b),—S(O)₂N(R^(a))(R^(b)), —CF₃, —OCF₃, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₂-C₆)alkenyl, optionally substituted(C₂-C₆)alkynyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted (C₁-C₁₀)heterocyclyl, or optionally substituted (C₆-C₁₀)aryl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or        optionally substituted (C₁-C₁₀)heteroaryl linked through a        nitrogen;

R³ is hydrogen, an optionally substituted bridged (C₅-C₁₂)cycloalkyl,optionally substituted bridged (C₂-C₁₀)heterocyclyl, optionallysubstituted (C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₃-C₈)cycloalkenyl, optionally substituted(C₆-C₁₀)aryl, optionally substituted (C₁-C₁₀)heteroaryl, optionallysubstituted (C₂-C₁₀)heterocyclyl; or

R³ is -A-D-E-G, wherein:

A is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—S—R^(e)—S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—;

D is an optionally substituted (C₁-C₈)alkylene, optionally substitutedbridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

E is a bond, —R^(e)—, R^(e)—C(O)—R^(e)—, R^(e)—C(O)C(O)—R^(e)—,R^(e)—C(O)O—R^(e)—, R^(e)—C(O)C(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, —R^(e)—C(O)N(R^(a))R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—OC(O)—R^(e)—, —R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—,—R^(e)—N(R^(a))S(O)₂—R^(e)—, or —R^(e)—S(O)₂N(R^(a))—R^(e)—; or

E is

where in all cases, E is linked to either a carbon or a nitrogen atom inD;

G is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —OC(O)N(R^(a)),—N(R^(a))C(O)N(R^(b))₂, —C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃,—N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), anoptionally substituted —(C₁-C₆)alkyl, an optionally substituted—(C₂-C₆)alkenyl, an optionally substituted —(C₂-C₆)alkynyl, anoptionally substituted —(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₁₀)heteroaryl, an optionally substituted —(C₁-C₁₀) heterocyclyl,an optionally substituted —(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R⁴ is a hydrogen, halogen, deuterium, an optionally substituted bridged(C₅-C₁₂)cycloalkyl group, optionally substituted bridged(C₂-C₁₀)heterocyclyl group, optionally substituted (C₁-C₈)alkyl,optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₈)cycloalkenyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted(C₂-C₁₀)heterocyclyl or -J-L-M-Q;

wherein:

J is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—;

L is a bond, an optionally substituted (C₁-C₈)alkylene, optionallysubstituted bridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

M is a bond, —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—,—R^(e)—C(O)O—R^(e)—, —R^(e)—OC(O)—R^(e), —R^(e)—C(O)C(O)N(R^(a))—R^(e)—,—R^(e)—N(R^(a))—C(O)C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,R^(e)—N(R^(a))C(O)—R^(e)—, R^(e)—C(O)N(R^(a))R^(e)—,R^(e)—OC(O)N(R^(a))—R^(e)—, R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—, or—R^(e)—S(O)₂N(R^(a))—R^(e)—; or

M is

where in all cases, M is linked to either a carbon or a nitrogen atom inL;

Q is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —N(R^(a))C(O)N(R^(b))₂,—C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b),—S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), an optionallysubstituted (C₁-C₆)alkyl, an optionally substituted (C₂-C₆)alkenyl, anoptionally substituted (C₂-C₆)alkynyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted (C₁-C₁₀)heteroaryl, anoptionally substituted (C₁-C₁₀) heterocyclyl, an optionally substituted(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R^(a) and R^(b) are each independently hydrogen, deuterium, anoptionally substituted (C₁-C₁₀)alkyl, an optionally substituted(C₂-C₁₀)alkenyl, an optionally substituted (C₂-C₁₀)alkynyl, anoptionally substituted —(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkyl, an optionallysubstituted (C₃-C₁₀)cycloalkyl, an optionally substituted (C₆-C₁₀)aryl,an optionally substituted (C₁-C₁₀)heteroaryl, an optionally substituted(C₁-C₁₀)heterocyclyl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl; and

R^(e) for each occurrence is independently a bond, an optionallysubstituted (C₁-C₁₀)alkylene, an optionally substituted(C₂-C₁₀)alkenylene, an optionally substituted (C₂-C₁₀)alkynylene, anoptionally substituted —(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkylene group, anoptionally substituted (C₃-C₁₀)cycloalkylene, an optionally substituted(C₆-C₁₀)arylene, an optionally substituted (C₁-C₁₀)heteroarylene, or anoptionally substituted (C₁-C₁₀)heterocyclylene.

In a sixty-fourth embodiment the invention provides the use of acompound of Formula 5

to form a compound of Formula (Id)

pharmaceutically acceptable salts, pro-drugs, biologically activemetabolites, stereoisomers and isomers thereof wherein

R^(p) is hydrogen, —SO₂N(CH₃)₂, —SO₂(2,4,6-trimethylphenyl),—SO₂-phenyl, —SO₂(4-butylphenyl), —SO₂(4-methylphenyl),—SO₂(4-methoxyphenyl), —C(O)OCH₂CCl₃, —C(O)OCH₂CH₂Si(CH₃)₃,—C(O)OC(CH₃)₃, —C(O)OC(CH₃)₂(CCl₃), —C(O)O-1-adamantyl, —CH═CH₂,—CH₂CH₂Cl, —CH(OCH₂CH₃)CH₃, —CH₂CH₂-2-pyridyl, —CH₂CH₂-4-pyridyl,—Si(C(CH₃)₃)(CH₃)₂, —Si(CH(CH₃)₂)₃, —CH₂-phenyl, —CH₂(4-CH₃O-phenyl),—CH₂(3,4-dimethoxyphenyl), —CH₂(2-nitrophenyl), -(2,4-dinitrophenyl),—CH₂C(O)phenyl, —C(phenyl)₃, —CH(phenyl)₂, —C(phenyl)₂(4-pyridyl),—N(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH(OCH₂CH₃)₂, —CH₂OCH₂CH₂Cl,—CH₂OCH₂CH₂Si(CH₃)₃, —CH₂OC(CH₃)₃, —CH₂OC(O)C(CH₃)₃, —CH₂OCH₂-phenyl,-(2-tetrahydropyranyl), —C(O)H, or —P(S)(phenyl)₂;

R¹, R² and R⁵ are each independently hydrogen, deuterium,—N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)),—C(O)R^(a), —C(OH)R^(a)R^(b), —N(R^(a))S(O)₂—R^(b),—S(O)₂N(R^(a))(R^(b)), —CF₃, —OCF₃, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₂-C₆)alkenyl, optionally substituted(C₂-C₆)alkynyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted (C₁-C₁₀)heterocyclyl, or optionally substituted (C₆-C₁₀)aryl;

wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen, R^(a) andR^(b) may form a ring such that —N(R^(a))(R^(b)) represents anoptionally substituted (C₂-C₁₀)heterocyclyl or optionally substituted(C₁-C₁₀)heteroaryl linked through a nitrogen;

R³ is hydrogen, an optionally substituted bridged (C₅-C₁₂)cycloalkyl,optionally substituted bridged (C₂-C₁₀)heterocyclyl, optionallysubstituted (C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₃-C₈)cycloalkenyl, optionally substituted(C₆-C₁₀)aryl, optionally substituted (C₁-C₁₀)heteroaryl, optionallysubstituted (C₂-C₁₀)heterocyclyl; or

R³ is -A-D-E-G, wherein:

A is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—;

D is an optionally substituted (C₁-C₈)alkylene, optionally substitutedbridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

E is a bond, —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—,—R^(e)—C(O)O—R^(e)—, R^(e)—C(O)C(O)N(R^(a))—R^(e)—,R^(e)—N(R^(a))C(O)C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, —R^(e)—C(O)N(R^(a))R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—OC(O)—R^(e)—, —R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—,—R^(e)—N(R^(a))S(O)₂—R^(e)—, or —R^(e)—S(O)₂N(R^(a))—R^(e)—; or

E is

where in all cases, E is linked to either a carbon or a nitrogen atom inD;

G is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —OC(O)N(R^(a)),—N(R^(a))C(O)N(R^(b))₂, —C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃,—N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), anoptionally substituted —(C₁-C₆)alkyl, an optionally substituted—(C₂-C₆)alkenyl, an optionally substituted —(C₂-C₆)alkynyl, anoptionally substituted —(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₁₀)heteroaryl, an optionally substituted —(C₁-C₁₀) heterocyclyl,an optionally substituted —(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkyl-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R⁴ and R⁶ are each independently a hydrogen, halogen, deuterium, anoptionally substituted bridged (C₅-C₁₂)cycloalkyl group, optionallysubstituted bridged (C₂-C₁₀)heterocyclyl group, optionally substituted(C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionallysubstituted (C₃-C₈)cycloalkenyl, optionally substituted (C₆-C₁₀)aryl,optionally substituted (C₁-C₁₀)heteroaryl, optionally substituted(C₂-C₁₀)heterocyclyl or -J-L-M-Q;

wherein:

J is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—S—R^(e)—S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—;

L is a bond, an optionally substituted (C₁-C₈)alkylene, optionallysubstituted bridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

M is a bond, —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—,—R^(e)—C(O)O—R^(e)—, —R^(e)—OC(O)—R^(e), —R^(e)—C(O)C(O)N(R^(a))—R^(e)—,—R^(e)—N(R^(a))—C(O)C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,R^(e)—N(R^(a))C(O)—R^(e)—, R^(e)—C(O)N(R^(a))R^(e)—,R^(e)—OC(O)N(R^(a))—R^(e)—, R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—, or—R^(e)—S(O)₂N(R^(a))—R^(e)—; or

M is

where in all cases, M is linked to either a carbon or a nitrogen atom inL;

Q is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —N(R^(a))C(O)N(R^(b))₂,—C(O—R^(a))(R^(b))₂, C(O)R^(a), —CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b),—S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), an optionallysubstituted (C₁-C₆)alkyl, an optionally substituted (C₂-C₆)alkenyl, anoptionally substituted (C₂-C₆)alkynyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted (C₁-C₁₀)heteroaryl, anoptionally substituted (C₁-C₁₀)heterocyclyl, an optionally substituted(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkyl-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R^(a) and R^(b) are each independently hydrogen, deuterium, anoptionally substituted (C₁-C₁₀)alkyl, an optionally substituted(C₂-C₁₀)alkenyl, an optionally substituted (C₂-C₁₀)alkynyl, anoptionally substituted —(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkyl, an optionallysubstituted (C₃-C₁₀)cycloalkyl, an optionally substituted (C₆-C₁₀)aryl,an optionally substituted (C₁-C₁₀)heteroaryl, an optionally substituted(C₁-C₁₀)heterocyclyl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl; and

R^(e) for each occurrence is independently a bond, an optionallysubstituted (C₁-C₁₀)alkylene, an optionally substituted(C₂-C₁₀)alkenylene, an optionally substituted (C₂-C₁₀)alkynylene, anoptionally substituted —(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkylene group, anoptionally substituted (C₃-C₁₀)cycloalkylene, an optionally substituted(C₆-C₁₀)arylene, an optionally substituted (C₁-C₁₀)heteroarylene, or anoptionally substituted (C₁-C₁₀)heterocyclylene

In a sixty-fifth embodiment the invention provides the use of a compoundof Formula 6

to prepare a compound of Formula (Ig) or Formula (If) or Formula (Ii)

pharmaceutically acceptable salts, pro-drugs, biologically activemetabolites, stereoisomers and isomers thereof wherein

R^(p) is a hydrogen, —SO₂N(CH₃)₂, —SO₂(2,4,6-trimethylphenyl),—SO₂-phenyl, —SO₂(4-butylphenyl), —SO₂(4-methylphenyl),—SO₂(4-methoxyphenyl), —C(O)OCH₂CCl₃, —C(O)OCH₂CH₂Si(CH₃)₃,—C(O)OC(CH₃)₃, —C(O)OC(CH₃)₂(CCl₃), —C(O)O-1-adamantyl, —CH═CH₂,—CH₂CH₂Cl, —CH(OCH₂CH₃)CH₃, —CH₂CH₂-2-pyridyl, —CH₂CH₂-4-pyridyl,—Si(C(CH₃)₃)(CH₃)₂, —Si(CH(CH₃)₂)₃, —CH₂-phenyl, —CH₂(4-CH₃O-phenyl),—CH₂(3,4-dimethoxyphenyl), —CH₂(2-nitrophenyl), -(2,4-dinitrophenyl),—CH₂C(O)phenyl, —C(phenyl)₃, —CH(phenyl)₂, —C(phenyl)₂(4-pyridyl),—N(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH(OCH₂CH₃)₂, —CH₂OCH₂CH₂Cl,—CH₂OCH₂CH₂Si(CH₃)₃, —CH₂OC(CH₃)₃, —CH₂OC(O)C(CH₃)₃, —CH₂OCH₂-phenyl,-(2-tetrahydropyranyl), —C(O)H, or —P(S)(phenyl)₂;

R^(x) is a hydrogen, fluorine, chlorine, bromine, iodine, —OS(O)₂CH₃,—OS(O)₂CF₃, —OS(O)₂phenyl, or —OS(O)₂(4-methylphenyl);

R¹, R² and R⁵ are each independently hydrogen, deuterium,—N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)),—C(O)R^(a), —C(OH)R^(a)R^(b), —N(R^(a))S(O)₂—R^(b),—S(O)₂N(R^(a))(R^(b)), —CF₃, —OCF₃, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₂-C₆)alkenyl, optionally substituted(C₂-C₆)alkynyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted (C₁-C₁₀)heterocyclyl, or optionally substituted (C₆-C₁₀)aryl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or        optionally substituted (C₁-C₁₀)heteroaryl linked through a        nitrogen;

R³ is hydrogen, an optionally substituted bridged (C₅-C₁₂)cycloalkyl,optionally substituted bridged (C₂-C₁₀)heterocyclyl, optionallysubstituted (C₁-C₈)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₃-C₈)cycloalkenyl, optionally substituted(C₆-C₁₀)aryl, optionally substituted (C₁-C₁₀)heteroaryl, optionallysubstituted (C₂-C₁₀)heterocyclyl; or

R³ is -A-D-E-G, wherein:

A is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—;

D is an optionally substituted (C₁-C₈)alkylene, optionally substitutedbridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

E is a bond, —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—,—R^(e)—C(O)O—R^(e)—, —R^(e)—C(O)C(O)N(R^(a))—R^(e)—,—R^(e)—N(R^(a))—C(O)C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)R^(e)—, —R^(e)—C(O)N(R^(a))R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e)—, R^(e)—N(R^(a))C(O)OR^(e)—,R^(e)—OC(O)—R^(e)—, —R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—,—R^(e)—N(R^(a))S(O)₂—R^(e)—, or —R^(e)—S(O)₂N(R^(a))—R^(e)—; or

E is

where in all cases, E is linked to either a carbon or a nitrogen atom inD;

G is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —OC(O)N(R^(a)),—N(R^(a))C(O)N(R^(b))₂, —C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃,—N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), anoptionally substituted —(C₁-C₆)alkyl, an optionally substituted—(C₂-C₆)alkenyl, an optionally substituted —(C₂-C₆)alkynyl, anoptionally substituted —(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₁₀)heteroaryl, an optionally substituted —(C₁-C₁₀) heterocyclyl,an optionally substituted —(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R⁶ is a hydrogen, halogen, deuterium, an optionally substituted bridged(C₅-C₁₂)cycloalkyl group, optionally substituted bridged(C₂-C₁₀)heterocyclyl group, optionally substituted (C₁-C₈)alkyl,optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₈)cycloalkenyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted(C₂-C₁₀)heterocyclyl or -J-L-M-Q;

wherein:

J is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene, optionallysubstituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene,optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—;

L is a bond, an optionally substituted (C₁-C₈)alkylene, optionallysubstituted bridged (C₅-C₁₂)cycloalkylene, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted bridged(C₅-C₁₀)cycloalkenylene, optionally substituted (C₃-C₁₀)cycloalkenylene,optionally substituted (C₆-C₁₀)arylene, optionally substituted(C₁-C₁₀)heteroarylene, optionally substituted bridged(C₂-C₁₀)heterocyclylene or an optionally substituted(C₂-C₁₀)heterocyclylene;

M is a bond, —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—,—R^(e)—C(O)O—R^(e)—, —R^(e)—OC(O)—R^(e), —R^(e)—C(O)C(O)N(R^(a))—R^(e)—,—R^(e)—N(R^(a))—C(O)C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,R^(e)—N(R^(a))C(O)—R^(e)—, R^(e)—C(O)N(R^(a))R^(e)—,R^(e)—OC(O)N(R^(a))—R^(e)—, R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—, or—R^(e)—S(O)₂N(R^(a))—R^(e)—; or

M is

where in all cases, M is linked to either a carbon or a nitrogen atom inL;

Q is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b), —N(R^(a))C(O)N(R^(b))₂,—C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b),—S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), an optionallysubstituted (C₁-C₆)alkyl, an optionally substituted (C₂-C₆)alkenyl, anoptionally substituted (C₂-C₆)alkynyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted (C₁-C₁₀)heteroaryl, anoptionally substituted (C₁-C₁₀) heterocyclyl, an optionally substituted(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl;

-   -   wherein in a moiety containing —N(R^(a))(R^(b)), the nitrogen,        R^(a) and R^(b) may form a ring such that —N(R^(a))(R^(b))        represents an optionally substituted (C₂-C₁₀)heterocyclyl or an        optionally substituted (C₁-C₁₀) heteroaryl linked through a        nitrogen;

R^(a) and R^(b) are each independently hydrogen, deuterium, anoptionally substituted (C₁-C₁₀)alkyl, an optionally substituted(C₂-C₁₀)alkenyl, an optionally substituted (C₂-C₁₀)alkynyl, anoptionally substituted (C₁-C₁₀)alkyl-O—(C₁-C₁₀)alkyl, an optionallysubstituted (C₃-C₁₀)cycloalkyl, an optionally substituted (C₆-C₁₀)aryl,an optionally substituted (C₁-C₁₀)heteroaryl, an optionally substituted(C₁-C₁₀)heterocyclyl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl; and

R^(e) for each occurrence is independently a bond, an optionallysubstituted (C₁-C₁₀)alkylene, an optionally substituted(C₂-C₁₀)alkenylene, an optionally substituted (C₂-C₁₀)alkynylene, anoptionally substituted —(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkylene group, anoptionally substituted (C₃-C₁₀)cycloalkylene, an optionally substituted(C₆-C₁₀)arylene, an optionally substituted (C₁-C₁₀)heteroarylene, or anoptionally substituted (C₁-C₁₀)heterocyclylene.

In a sixty-sixth embodiment the invention provides a pharmaceuticalcomposition comprising a compound of Formula (I) as defined in claim 1

a pharmaceutically acceptable carrier and excipient and a secondtherapeutic agent selected from the group consisting of cytokinesuppressive anti-inflammatory drugs, antibodies to or antagonists ofother human cytokines or growth factors, IL-1, IL-2, IL-3, IL-4, IL-5,IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons,EMAP-II, GM-CSF, FGF, PDGF, CTLA or their ligands including CD154,HUMIRA™, REMICADE™, SIMPONI™ (golimumab), CIMZIA™, ACTEMRA™, CDP 571,soluble p55 or p75 TNF receptors, ENBREL™, Lenercept, TNFα convertingenzyme inhibitors, IL-1 inhibitors, Interleukin 11, IL-18 antagonists,IL-12 antagonists, IL-12 antibodies, soluble IL-12 receptors, IL-12binding proteins, non-depleting anti-CD4 inhibitors FK506, rapamycin,mycophenolate mofetil, leflunomide, NSAIDs, ibuprofen, corticosteroids,phosphodiesterase inhibitors, adensosine agonists, antithromboticagents, complement inhibitors, adrenergic agents, IL-1β convertingenzyme inhibitors, T-cell signalling kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurines,derivatives p75TNFRIgG, sIL-1RI, sIL-1RII, sIL-6R, celecoxib,hydroxychloroquine sulfate, rofecoxib, infliximab, naproxen, valdecoxib,sulfasalazine, meloxicam, acetate, gold sodium thiomalate, aspirin,triamcinolone acetonide, propoxyphene napsylate/apap, folate,nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium,oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenacsodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate,sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronatesodium, morphine sulfate, lidocaine hydrochloride, indomethacin,glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine, oxycodoneHCl/acetaminophen, olopatadine HCl misoprostol, naproxen sodium,omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18BP, anti-IL-12, anti-IL15, VX-740, Roflumilast, IC-485, CDC-801, SiPiagonists, FTY720, PKC family inhibitors, Ruboxistaurin, AEB-071,Mesopram, methotrexate, leflunomide, corticosteroids, budenoside,dexamethasone, sulfasalazine, 5-aminosalicylic acid, olsalazine, IL-1βconverting enzyme inhibitors, IL-Ira, T cell signaling inhibitors,tyrosine kinase inhibitors, 6-mercaptopurines, IL-11, mesalamine,prednisone, azathioprine, mercaptopurine, infliximab, methylprednisolonesodium succinate, diphenoxylate/atrop sulfate, loperamide hydrochloride,omeprazole, folate, ciprofloxacin/dextrose-water, hydrocodone,bitartrate/apap, tetracycline hydrochloride, fluocinonide,metronidazole, thimerosal/boric acid, cholestyramine/sucrose,ciprofloxacin hydrochloride, hyoscyamine sulfate, meperidinehydrochloride, midazolam hydrochloride, oxycodone HCl/acetaminophen,promethazine hydrochloride, sodium phosphate,sulfamethoxazole/trimethoprim, polycarbophil, propoxyphene napsylate,hydrocortisone, multivitamins, balsalazide disodium, codeinephosphate/apap, colesevelam HCl, cyanocobalamin, folic acid,levofloxacin, natalizumab, interferon-gamma, methylprednisolone,azathioprine, cyclophosphamide, cyclosporine, methotrexate,4-aminopyridine, tizanidine, interferon-β1a, AVONEX®, interferon-β1b,BETASERON®, interferon α-n3, interferon-α, interferon β1A-IF,Peginterferon α 2b, Copolymer 1, COPAXONE®, hyperbaric oxygen,intravenous immunoglobulin, cladribine, cyclosporine, FK506,mycophenolate mofetil, leflunomide, NSAIDs, corticosteroids,prednisolone, phosphodiesterase inhibitors, adensosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents,antiinflammatory cytokines, interferon-β, IFNβ1a, IFNβ1b, copaxone,corticosteroids, caspase inhibitors, inhibitors of caspase-1, antibodiesto CD40 ligand and CD80, alemtuzumab, dronabinol, daclizumab,mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate,natalizumab, sinnabidol, α-immunokine NNSO3, ABR-215062, AnergiX.MS,chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189,liposome encapsulated mitoxantrone, THC.CBD, cannabinoid agonists,MBP-8298, mesopram, MNA-715, anti-IL-6 receptor antibody, neurovax,pirfenidone allotrap 1258 (RDP-1258), sTNF-R1, talampanel,teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists, interferongamma antagonists, IL-4 agonists, diclofenac, misoprostol, naproxen,meloxicam, indomethacin, diclofenac, methotrexate, azathioprine,minocyclin, prednisone, etanercept, rofecoxib, sulfasalazine, naproxen,leflunomide, methylprednisolone acetate, indomethacin,hydroxychloroquine sulfate, prednisone, sulindac, betamethasone dipropaugmented, infliximab, methotrexate, folate, triamcinolone acetonide,diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen,meloxicam, methylprednisolone, nabumetone, tolmetin sodium,calcipotriene, cyclosporine, diclofenac sodium/misoprostol,fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodonebitartrate/apap, risedronate sodium, sulfadiazine, thioguanine,valdecoxib, alefacept, and efalizumab, diclofenac, naproxen, ibuprofen,piroxicam, indomethacin, COX2 inhibitors, rofecoxib, valdecoxib,hydroxychloroquine, steroids, prednisolone, budenoside, dexamethasone,cytotoxics, azathioprine, cyclophosphamide, mycophenolate mofetil,inhibitors of PDE4, purine synthesis inhibitor, sulfasalazine,5-aminosalicylic acid, olsalazine, Imuran®, CTLA-4-IgG, anti-B7 familyantibodies, anti-PD-1 family antibodies, anti-cytokine antibodies,fonotolizumab, anti-IFNg antibody, anti-receptor receptor antibodies,anti-IL-6 receptor antibody, antibodies to B-cell surface molecules, LJP394, Rituximab, anti-CD20 antibody and lymphostat-B.

DETAILED DESCRIPTION OF THE INVENTION

Protein kinases are a broad and diverse class, of over 500 enzymes, thatinclude oncogenes, growth factors receptors, signal transductionintermediates, apoptosis related kinases and cyclin dependent kinases.They are responsible for the transfer of a phosphate group to specifictyrosine, serine or threonine amino acid residues, and are broadlyclassified as tyrosine and serine/threonine kinases as a result of theirsubstrate specificity.

The Jak family kinases (Jak1, Jak2, Jak3 and Tyk2) are cytoplasmictyrosine kinases that associate with membrane bound cytokine receptors.Cytokine binding to their receptor initiates Jak kinase activation viatrans and autophosphorylation processes. The activated Jak kinasesphosphorylate residues on the cytokine receptors creatingphosphotyrosine binding sites for SH2 domain containing proteins such asSignal Transduction Activators of Transcript (STAT) factors and othersignal regulators transduction such as SOCS proteins and SHIPphosphatases. Activation of STAT factors via this process leads to theirdimerization, nuclear translocation and new mRNA transcription resultingin expression of immunocyte proliferation and survival factors as wellas additional cytokines, chemokines and molecules that facilitatecellular trafficking (see Journal of Immunology, 2007, 178, p. 2623).Jak kinases transduce signals for many different cytokine families andhence potentially play roles in diseases with widely differentpathologies including but not limited to the following examples. BothJak1 and Jak3 control signaling of the so-called common gamma chaincytokines (IL2, IL4, IL7, IL9, IL15 and IL21), hence simultaneousinhibition of either Jak1 or Jak3 could be predicted to impact Th1mediated diseases such as rheumatoid arthritis via blockade of IL2, IL7and IL15 signaling. On the other hand, IL2 signaling has recently beenshown to be essential for development and homeostasis of T-regulatorycells (Malek T R et al., Immunity, 2002, 17(2), p. 167-78). Thus, basedon genetic data, blockade of IL2 signaling alone is predicted to resultin autoimmunity (Yamanouchi J et al., Nat. Genet., 2007, 39(3), p.329-37, and Willerford D M et al., Immunity, 1995, 3(4), p. 521-30). Th2mediated diseases such as asthma or atopic dermatitis via IL4 and IL9signaling blockade. Jak1 and Tyk2 mediate signaling of IL13 (see Int.Immunity, 2000, 12, p. 1499). Hence, blockade of these may also bepredicted to have a therapeutic effect in asthma. These two kinases arealso thought to mediate Type I interferon signaling; their blockadecould therefore be predicted to reduce the severity of systemic lupuserythematosus (SLE). Tyk2 and Jak2 mediate signaling of IL12 and IL23.In fact, blockade of these cytokines using monoclonal antibodies hasbeen effective in treating psoriasis. Therefore blockade of this pathwayusing inhibitors of these kinases could be predicted to be effective inpsoriasis as well. In summary, this invention describes small-moleculecompounds that inhibit, regulate and/or modulate Jak family kinaseactivity that is pivotal to several mechanisms thought critical to theprogression of autoimmune diseases including, but not limited to,rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiplesclerosis (MS), Crohn's disease, psoriasis and asthma.

Several pathologically significant cytokines signal via Jak1 alone(Guschin D, et al., EMBO J. 1995 Apr. 3; 14(7):1421-9; Parganas E, etal., Cell. 1998 May 1; 93(3):385-95; Rodig S. J., et al., Cell. 1998 May1; 93(3):373-83). Blockade of one of these, IL6, using an IL6Rneutralizing antibody, has been shown to significantly improve diseasescores in human rheumatoid arthritis patients (Nishimoto N. et al., AnnRheum Dis., 2007, 66(9), p. 1162-7). Similarly, blockaded of GCSFsignaling, which is also mediated by Jak1 alone, using neutralizingmonoclonal antibodies or target gene deletion protects mice fromexperimental arthritis (Lawlor K. E. et al., Proc Natl Acad Sci U.S.A.,2004, 101(31), p. 11398-403). Accordingly, the identification ofsmall-molecule compounds that inhibit, regulate and/or modulate thesignal transduction of kinases, such as Jak1, is a desirable means toprevent or treat autoimmune diseases or other diseases related toabberant Jak1 function.

Jak2 is also activated in a wide variety of human cancers such asprostate, colon, ovarian and breast cancers, melanoma, leukemia andother haematopoietic malignancies. In addition, somatic point mutationof the Jak2 gene has been identified to be highly associated withclassic myeloproliferative disorders (MPD) and infrequently in othermyeloid disorders. Constitutive activation of Jak2 activity is alsocaused by chromosomal translocation in hematopoeitic malignancies. Ithas also been shown that inhibition of the Jak/STAT pathway, and inparticular inhibition of Jak2 activity, results in anti-proliferativeand pro-apoptotic effects largely due to inhibition of phosphorylationof STAT. Furthermore, pharmacological modulation or inhibition of Jak2activity could effectively block tumor growth and induce apoptosis byreducing the STAT phosphorylation in cell culture and human tumorxenografts in vivo. Accordingly, the identification of small-moleculecompounds that inhibit, regulate and/or modulate the signal transductionof kinases, particularly Jak2, is desirable as a means to treat orprevent diseases and conditions associated with cancers.

Jak kinases also transmit signals regulating essential physiologicalprocesses whose inhibition could be undesirable. For example Jak2mediates the signaling of Erythropoetin (Epo) andGranulocyte/Monocyte-Colony Stimulating Factor. Individuals withgenetic, congenital or acquired defects in these signaling pathways candevelop potentially life-threatening complications such as anemia andneutrophil dysfunction. Accordingly, one non-limiting aspect of thisinvention also relates to a method to identify compounds that may have afavorable safety profile as a result of them selectively avoidinginhibition of Jak2.

The protein kinase C family is a group of serine/threonine kinases thatcomprises twelve related isoenzymes. Its members are encoded bydifferent genes and are sub-classified according to their requirementsfor activation. The classical enzymes (cPKC) require diacylglycerol(DAG), phosphatidylserine (PS) and calcium for activation. The novelPKC's (nPKC) require DAG and PS but are calcium independent. Theatypical PKC's (aPKC) do not require calcium or DAG.

PKCtheta is a member of the nPKC sub-family (Baier, G., et al., J. Biol.Chem., 1993, 268, 4997). It has a restricted expression pattern, foundpredominantly in T cells and skeletal muscle (Mischak, H. et al., FEBSLett., 1993, 326, p. 51), with some expression reported in mast cells(Liu, Y. et al., J. Leukoc. Biol., 2001, 69, p. 831) and endothelialcells (Mattila, P. et al., Life Sci., 1994, 55, p. 1253).

Upon T cell activation, a supramolecular activation complex (SMAC) formsat the site of contact between the T cell and the antigen presentingcell (APC). PKCtheta is the only PKC isoform found to localize at theSMAC (Monks, C. et al., Nature, 1997, 385, 83), placing it in proximitywith other signaling enzymes that mediate T cell activation processes.

In another study (Baier-Bitterlich, G. et al., Mol. Cell. Biol., 1996,16, 842) the role of PKCtheta in the activation of AP-1, a transcriptionfactor important in the activation of the IL-2 gene, was confirmed. Inunstimulated T cells, constitutively active PKCtheta stimulated AP-1activity while in cells with dominant negative PKCtheta, AP-1 activitywas not induced upon activation by PMA.

Other studies showed that PKCtheta, via activation of IκB kinase beta,mediates activation of NF-κB induced by T cell receptor/CD28co-stimulation (N. Coudronniere et al., Proc. Nat. Acad. Sci. U.S.A.,2000, 97, p. 3394; and Lin, X. et al., Mol. Cell. Biol., 2000, 20, p.2933).

Proliferation of peripheral T cells from PKCtheta knockout mice, inresponse to T cell receptor (TCR)/CD28 stimulation was greatlydiminished compared to T cells from wild type mice. In addition, theamount of IL-2 released from the T cells was also greatly reduced (Sun,Z. et al., Nature, 2000, 404, p. 402). It has also been shown thatPKCtheta-deficient mice show impaired pulmonary inflammation and airwayhyperresponsiveness (AHR) in a Th2-dependent murine asthma model, withno defects in viral clearance and Th1-dependent cytotoxic T cellfunction (Berg-Brown, N. N. et al., J. Exp. Med., 2004, 199, p. 743;Marsland, B. J. et al., J. Exp. Med., 2004, 200, p. 181). The impairedTh2 cell response results in reduced levels of IL-4 and immunoglobulin E(IgE), contributing to the AHR and inflammatory pathophysiology.Otherwise, the PKCtheta knockout mice seemed normal and fertile.

Evidence also exists that PKCtheta participates in the IgE receptor(FcεRI)-mediated response of mast cells (Liu, Y. et al., J. Leukoc.Biol., 2001, 69, p. 831). In human-cultured mast cells (HCMC), it hasbeen demonstrated that PKC kinase activity rapidly localizes to themembrane following FcεRI cross-linking (Kimata, M. et al., Biochem.Biophys. Res. Commun., 1999, 257(3), p. 895). A recent study examiningin vitro activity of bone marrow mast cells (BMMC) derived fromwild-type and PKCtheta-deficient mice shows that upon FceRI crosslinking, BMMCs from PKCtheta-deficient mice reduced levels of IL-6,tumor necrosis factor-alpha (TNFα) and IL-13 in comparison with BMMCsfrom wild-type mice, suggesting a potential role for PKCtheta in mastcell cytokine production in addition to T cell activation (Ciarletta, A.B. et al., poster presentation at the 2005 American Thoracic SocietyInternational Conference).

The studies cited above and others studies confirm the critical role ofPKCtheta in T cells activation and in mast cell (MC) signaling. Thus aninhibitor of PKCtheta would be of therapeutic benefit in treatingimmunological disorders and other diseases mediated by the inappropriateactivation of T cells and MC signaling.

Many of the kinases, whether a receptor or non-receptor tyrosine kinaseor a S/T kinase have been found to be involved in cellular signalingpathways involved in numerous pathogenic conditions, includingimmunomodulation, inflammation, or proliferative disorders such ascancer.

Many autoimmune diseases and disease associated with chronicinflammation, as well as acute responses, have been linked to excessiveor unregulated production or activity of one or more cytokines.

The compounds of the invention are also useful in the treatment ofcardiovascular disorders, such as acute myocardial infarction, acutecoronary syndrome, chronic heart failure, myocardial infarction,atherosclerosis, viral myocarditis, cardiac allograft rejection, andsepsis-associated cardiac dysfunction. Furthermore, the compounds of thepresent invention are also useful for the treatment of central nervoussystem disorders such as meningococcal meningitis, Alzheimer's diseaseand Parkinson's disease.

The compounds of the invention are also useful in the treatment of anocular condition, a cancer, a solid tumor, a sarcoma, fibrosarcoma,osteoma, melanoma, retinoblastoma, a rhabdomyosarcoma, glioblastoma,neuroblastoma, teratocarcinoma, hypersensitivity reactions, hyperkineticmovement disorders, hypersensitivity pneumonitis, hypertension,hypokinetic movement disorders, aordic and peripheral aneuryisms,hypothalamic-pituitary-adrenal axis evaluation, aortic dissection,arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia,spinocerebellar degenerations, streptococcal myositis, structurallesions of the cerebellum, Subacute sclerosing panencephalitis, Syncope,syphilis of the cardiovascular system, systemic anaphalaxis, systemicinflammatory response syndrome, systemic onset juvenile rheumatoidarthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans,transplants, trauma/hemorrhage, type III hypersensitivity reactions,type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria,valvular heart diseases, varicose veins, vasculitis, venous diseases,venous thrombosis, ventricular fibrillation, viral and fungalinfections, vital encephalitis/aseptic meningitis, vital-associatedhemaphagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease,xenograft rejection of any organ or tissue, heart transplant rejection,hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolyticthrombocytopenic purpura, hemorrhage, idiopathic pulmonary fibrosis,antibody mediated cytotoxicity, Asthenia, infantile spinal muscularatrophy, inflammation of the aorta, influenza A, ionizing radiationexposure, iridocyclitis/uveitis/optic neuritis, juvenile spinal muscularatrophy, lymphoma, myeloma, leukaemia, malignant ascites, hematopoieticcancers, a diabetic condition such as insulin-dependent diabetesmellitus glaucoma, diabetic retinopathy or microangiopathy, sickle cellanaemia, chronic inflammation, glomerulonephritis, graft rejection, Lymedisease, von Hippel Lindau disease, pemphigoid, Paget's disease,fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome,Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthmaor edema following burns, trauma, radiation, stroke, hypoxia, ischemia,ovarian hyperstimulation syndrome, post perfusion syndrome, post pumpsyndrome, post-MI cardiotomy syndrome, preeclampsia, menometrorrhagia,endometriosis, pulmonary hypertension, infantile hemangioma, orinfection by Herpes simplex, Herpes Zoster, human immunodeficiencyvirus, parapoxvirus, protozoa or toxoplasmosis, progressive supranucleopalsy, primary pulmonary hypertension, radiation therapy, Raynaud'sphenomenon, Raynaud's disease, Refsum's disease, regular narrow QRStachycardia, renovascular hypertension, restrictive cardiomyopathy,sarcoma, senile chorea, senile dementia of Lewy body type, shock, skinallograft, skin changes syndrome, ocular or macular edema, ocularneovascular disease, scleritis, radial keratotomy, uveitis, vitritis,myopia, optic pits, chronic retinal detachment, post-laser treatmentcomplications, conjunctivitis, Stargardt's disease, Eales disease,retinopathy, macular degeneration, restenosis, ischemia/reperfusioninjury, ischemic stroke, vascular occlusion, carotid obstructivedisease, ulcerative colitis, inflammatory bowel disease, diabetes,diabetes mellitus, insulin dependent diabetes mellitus, allergicdiseases, dermatitis scleroderma, graft versus host disease, organtransplant rejection (including but not limited to bone marrow and solidorgan rejection), acute or chronic immune disease associated with organtransplantation, sarcoidosis, disseminated intravascular coagulation,Kawasaki's disease, nephrotic syndrome, chronic fatigue syndrome,Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopicvasculitis of the kidneys, chronic active hepatitis, septic shock, toxicshock syndrome, sepsis syndrome, cachexia, infectious diseases,parasitic diseases, acquired immunodeficiency syndrome, acute transversemyelitis, Huntington's chorea, stroke, primary biliary cirrhosis,hemolytic anemia, malignancies, Addison's disease, idiopathic Addison'sdisease, sporadic, polyglandular deficiency type I and polyglandulardeficiency type II, Schmidt's syndrome, adult (acute) respiratorydistress syndrome, alopecia, alopecia greata, seronegative arthopathy,arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative coliticarthropathy, enteropathic synovitis, chlamydia, yersinia and salmonellaassociated arthropathy, atheromatous disease/arteriosclerosis, atopicallergy, autoimmune bullous disease, pemphigus vulgaris, pemphigusfoliaceus, pemphigoid, linear IgA disease, autoimmune haemolyticanaemia, Coombs positive haemolytic anaemia, acquired perniciousanaemia, juvenile pernicious anaemia, peripheral vascular disorders,peritonitis, pernicious anemia, myalgic encephalitis/Royal Free Disease,chronic mucocutaneous candidiasis, giant cell arteritis, primarysclerosing hepatitis, cryptogenic autoimmune hepatitis, AcquiredImmunodeficiency Disease Syndrome, Acquired Immunodeficiency RelatedDiseases, Hepatitis A, Hepatitis B, Hepatitis C, His bundle arrythmias,HIV infection/HIV neuropathy, common varied immunodeficiency (commonvariable hypogammaglobulinaemia), dilated cardiomyopathy, femaleinfertility, ovarian failure, premature ovarian failure, fibrotic lungdisease, chronic wound healing, cryptogenic fibrosing alveolitis,post-inflammatory interstitial lung disease, interstitial pneumonitis,pneumocystis carinii pneumonia, pneumonia, connective tissue diseaseassociated interstitial lung disease, mixed connective tissue disease,associated lung disease, systemic sclerosis associated interstitial lungdisease, rheumatoid arthritis associated interstitial lung disease,systemic lupus erythematosus associated lung disease,dermatomyositis/polymyositis associated lung disease, Sjögren's diseaseassociated lung disease, ankylosing spondylitis associated lung disease,vasculitic diffuse lung disease, haemosiderosis associated lung disease,drug-induced interstitial lung disease, radiation fibrosis,bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocyticinfiltrative lung disease, postinfectious interstitial lung disease,gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis(classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis(anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type Binsulin resistance with acanthosis nigricans, hypoparathyroidism, acuteimmune disease associated with organ transplantation, chronic immunedisease associated with organ transplantation, osteoarthritis, primarysclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathicleucopaenia, autoimmune neutropaenia, renal disease NOS,glomerulonephritides, microscopic vasulitis of the kidneys, Lymedisease, discoid lupus erythematosus, male infertility idiopathic orNOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympatheticophthalmia, pulmonary hypertension secondary to connective tissuedisease, acute and chronic pain (different forms of pain), Goodpasture'ssyndrome, pulmonary manifestation of polyarteritis nodosa, acuterheumatic fever, rheumatoid spondylitis, Still's disease, systemicsclerosis, Sjögren's syndrome, Takayasu's disease/arteritis, autoimmunethrombocytopaenia, toxicity, transplants, and diseases involvinginappropriate vascularization for example diabetic retinopathy,retinopathy of prematurity, choroidal neovascularization due toage-related macular degeneration, and infantile hemangiomas in humanbeings. In addition, such compounds may be useful in the treatment ofdisorders such as ascites, effusions, and exudates, including forexample macular edema, cerebral edema, acute lung injury, adultrespiratory distress syndrome (ARDS), proliferative disorders such asrestenosis, fibrotic disorders such as hepatic cirrhosis andatherosclerosis, mesangial cell proliferative disorders such as diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathysyndromes, and glomerulopathies, myocardial angiogenesis, coronary andcerebral collaterals, ischemic limb angiogenesis, ischemia/reperfusioninjury, peptic ulcer Helicobacter related diseases, virally-inducedangiogenic disorders, preeclampsia, menometrorrhagia, cat scratch fever,rubeosis, neovascular glaucoma and retinopathies such as thoseassociated with diabetic retinopathy, retinopathy of prematurity, orage-related macular degeneration. In addition, these compounds can beused as active agents against hyperproliferative disorders such asthyroid hyperplasia (especially Grave's disease), and cysts (such ashypervascularity of ovarian stroma characteristic of polycystic ovariansyndrome (Stein-Leventhal syndrome) and polycystic kidney disease sincesuch diseases require a proliferation of blood vessel cells for growthand/or metastasis.

Compounds of Formula (I) of the invention can be used alone or incombination with an additional agent, e.g., a therapeutic agent, saidadditional agent being selected by the skilled artisan for its intendedpurpose. For example, the additional agent can be a therapeutic agentart-recognized as being useful to treat the disease or condition beingtreated by the compound of the present invention. The additional agentalso can be an agent that imparts a beneficial attribute to thetherapeutic composition e.g., an agent that affects the viscosity of thecomposition.

It should further be understood that the combinations which are to beincluded within this invention are those combinations useful for theirintended purpose. The agents set forth below are illustrative forpurposes and not intended to be limited. The combinations, which arepart of this invention, can be the compounds of the present inventionand at least one additional agent selected from the lists below. Thecombination can also include more than one additional agent, e.g., twoor three additional agents if the combination is such that the formedcomposition can perform its intended function.

Preferred combinations are non-steroidal anti-inflammatory drug(s) alsoreferred to as NSAIDS which include drugs like ibuprofen. Otherpreferred combinations are corticosteroids including prednisolone; thewell known side-effects of steroid use can be reduced or even eliminatedby tapering the steroid dose required when treating patients incombination with the compounds of this invention. Non-limiting examplesof therapeutic agents for rheumatoid arthritis with which a compound ofFormula (I) of the invention can be combined include the following:cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies toor antagonists of other human cytokines or growth factors, for example,TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-15,IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF.Compounds of the invention can be combined with antibodies to cellsurface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40,CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligandsincluding CD154 (gp39 or CD40L).

Preferred combinations of therapeutic agents may interfere at differentpoints in the autoimmune and subsequent inflammatory cascade; preferredexamples include TNF antagonists like chimeric, humanized or human TNFantibodies, D2E7 (U.S. Pat. No. 6,090,382, HUMIRA™), CA2 (REMICADE™),SIMPONI™ (golimumab), CIMZIA™, ACTEMRA™, CDP 571, and soluble p55 or p75TNF receptors, derivatives, thereof, (p75TNFRIgG (ENBREL™) or p55TNFRIgG(Lenercept), and also TNFα converting enzyme (TACE) inhibitors;similarly IL-1 inhibitors (Interleukin-1-converting enzyme inhibitors,IL-IRA etc.) may be effective for the same reason. Other preferredcombinations include Interleukin 11. Yet other preferred combinationsare the other key players of the autoimmune response which may actparallel to, dependent on or in concert with IL-18 function; especiallypreferred are IL-12 antagonists including IL-12 antibodies or solubleIL-12 receptors, or IL-12 binding proteins. It has been shown that IL-12and IL-18 have overlapping but distinct functions and a combination ofantagonists to both may be most effective. Yet another preferredcombination is non-depleting anti-CD4 inhibitors. Yet other preferredcombinations include antagonists of the co-stimulatory pathway CD80(B7.1) or CD86 (B7.2) including antibodies, soluble receptors orantagonistic ligands.

A compound of Formula (I) of the invention may also be combined withagents, such as methotrexate, 6-MP, azathioprine sulphasalazine,mesalazine, olsalazine chloroquinine/hydroxychloroquine, pencillamine,aurothiomalate (intramuscular and oral), azathioprine, cochicine,corticosteroids (oral, inhaled and local injection), beta-2adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines(theophylline, aminophylline), cromoglycate, nedocromil, ketotifen,ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolatemofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroidssuch as prednisolone, phosphodiesterase inhibitors, adensosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents, agentswhich interfere with signalling by proinflammatory cytokines such asTNFα or IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1βconverting enzyme inhibitors, T-cell signalling inhibitors such askinase inhibitors, metalloproteinase inhibitors, sulfasalazine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors and the derivatives p75TNFRIgG (Enbrel™) and p55TNFRIgG(Lenercept), sIL-1RI, sIL-1RII, sIL-6R), antiinflammatory cytokines(e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ), celecoxib, folic acid,hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, naproxen,valdecoxib, sulfasalazine, methylprednisolone, meloxicam,methylprednisolone acetate, gold sodium thiomalate, aspirin,triamcinolone acetonide, propoxyphene napsylate/apap, folate,nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium,oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenacsodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate,sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronatesodium, prednisolone, morphine sulfate, lidocaine hydrochloride,indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl,sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl misoprostol,naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP,MRA, CTLA4-IG, IL-18 BP, anti-IL-12, Anti-IL15, BIRB-796, SCIO-469,VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, S1P1 agonists(such as FTY720), PKC family inhibitors (such as Ruboxistaurin orAEB-071) and Mesopram. Preferred combinations include methotrexate orleflunomide and in moderate or severe rheumatoid arthritis cases,cyclosporine and anti-TNF antibodies as noted above.

Non-limiting examples of therapeutic agents for inflammatory boweldisease with which a compound of Formula (I) of the invention can becombined include the following: budenoside; epidermal growth factor;corticosteroids; cyclosporin, sulfasalazine; aminosalicylates;6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors;mesalamine; olsalazine; balsalazide; antioxidants; thromboxaneinhibitors; IL-1 receptor antagonists; anti-IL-1β monoclonal antibodies;anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors;pyridinyl-imidazole compounds; antibodies to or antagonists of otherhuman cytokines or growth factors, for example, TNF, LT, IL-1, IL-2,IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF, andPDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28,CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate;cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide;NSAIDs, for example, ibuprofen; corticosteroids such as prednisolone;phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents;complement inhibitors; adrenergic agents; agents which interfere withsignalling by proinflammatory cytokines such as TNFα or IL-1 (e.g. NIK,IKK, or MAP kinase inhibitors); IL-1β converting enzyme inhibitors;TNFαc converting enzyme inhibitors; T-cell signalling inhibitors such askinase inhibitors; metalloproteinase inhibitors; sulfasalazine;azathioprine; 6-mercaptopurines; angiotensin converting enzymeinhibitors; soluble cytokine receptors and derivatives thereof (e.g.soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) andantiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ).Preferred examples of therapeutic agents for Crohn's disease with whicha compound of Formula (I) can be combined include the following: TNFantagonists, for example, anti-TNF antibodies, D2E7 (U.S. Pat. No.6,090,382, HUMIRA™), CA2 (REMICADE™), CDP 571, TNFR-Ig constructs,(p75TNFRIgG (ENBREL™) and p55TNFRIgG (LENERCEPT™) inhibitors and PDE4inhibitors. A compound of Formula (I) can be combined withcorticosteroids, for example, budenoside and dexamethasone;sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents whichinterfere with synthesis or action of proinflammatory cytokines such asIL-1, for example, IL-1β converting enzyme inhibitors and IL-Ira; T cellsignaling inhibitors, for example, tyrosine kinase inhibitors6-mercaptopurines; IL-11; mesalamine; prednisone; azathioprine;mercaptopurine; infliximab; methylprednisolone sodium succinate;diphenoxylate/atrop sulfate; loperamide hydrochloride; methotrexate;omeprazole; folate; ciprofloxacin/dextrose-water; hydrocodonebitartrate/apap; tetracycline hydrochloride; fluocinonide;metronidazole; thimerosal/boric acid; cholestyramine/sucrose;ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidinehydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen;promethazine hydrochloride; sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap; colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis withwhich a compound of Formula (I) can be combined include the following:corticosteroids; prednisolone; methylprednisolone; azathioprine;cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine;tizanidine; interferon-β1a (AVONEX®; Biogen); interferon-β1b(BETASERON®; Chiron/Berlex); interferon α-n3) (InterferonSciences/Fujimoto), interferon-α (Alfa Wassermann/J&J), interferonβ1A-IF (Serono/Inhale Therapeutics), Peginterferon α 2b(Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; TevaPharmaceutical Industries, Inc.); hyperbaric oxygen; intravenousimmunoglobulin; cladribine; antibodies to or antagonists of other humancytokines or growth factors and their receptors, for example, TNF, LT,IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II,GM-CSF, FGF, and PDGF. A compound of Formula (I) can be combined withantibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19,CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or theirligands. A compound of Formula (I) may also be combined with agents suchas methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil,leflunomide, an SiPi agonist, NSAIDs, for example, ibuprofen,corticosteroids such as prednisolone, phosphodiesterase inhibitors,adensosine agonists, antithrombotic agents, complement inhibitors,adrenergic agents, agents which interfere with signalling byproinflammatory cytokines such as TNFα, or IL-1 (e.g., NIK, IKK, p38 orMAP kinase inhibitors), IL-1β converting enzyme inhibitors, TACEinhibitors, T-cell signaling inhibitors such as kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, azathioprine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory cytokines(e.g. IL-4, IL-10, IL-13 and TGFβ).

Preferred examples of therapeutic agents for multiple sclerosis in whicha compound of Formula (I) can be combined to include interferon-β, forexample, IFNβ1a and IFNβ1b; copaxone, corticosteroids, caspaseinhibitors, for example inhibitors of caspase-1, IL-1 inhibitors, TNFinhibitors, and antibodies to CD40 ligand and CD80.

A compound of Formula (I) may also be combined with agents, such asalemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliprodenhydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol,α-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptorantagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulatedmitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidoneallotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2,tiplimotide, VLA-4 antagonists (for example, TR-14035, VLA4 Ultrahaler,Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.

Non-limiting examples of therapeutic agents for ankylosing spondylitiswith which a compound of Formula (I) can be combined include thefollowing: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam,indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine,methotrexate, azathioprine, minocyclin, prednisone, and anti-TNFantibodies, D2E7 (U.S. Pat. No. 6,090,382; HUMIRA™), CA2 (REMICADE™),CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBREL™) and p55TNFRIgG(LENERCEPT™)

Non-limiting examples of therapeutic agents for asthma with which acompound of Formula (I) can be combined include the following:albuterol, salmeterol/fluticasone, montelukast sodium, fluticasonepropionate, budesonide, prednisone, salmeterol xinafoate, levalbuterolHCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate,triamcinolone acetonide, beclomethasone dipropionate, ipratropiumbromide, azithromycin, pirbuterol acetate, prednisolone, theophyllineanhydrous, methylprednisolone sodium succinate, clarithromycin,zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillintrihydrate, flunisolide, allergy injection, cromolyn sodium,fexofenadine hydrochloride, flunisolide/menthol,amoxicillin/clavulanate, levofloxacin, inhaler assist device,guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl,doxycycline hyclate, guaifenesin/d-methorphan,p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride,mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin,pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed,phenylephrine/cod/promethazine, codeine/promethazine, cefprozil,dexamethasone, guaifenesin/pseudoephedrine,chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate,epinephrine, methylprednisolone, anti-IL-13 antibody, and metaproterenolsulfate.

Non-limiting examples of therapeutic agents for COPD with which acompound of Formula (I) can be combined include the following: albuterolsulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone,albuterol, salmeterol xinafoate, fluticasone propionate, prednisone,theophylline anhydrous, methylprednisolone sodium succinate, montelukastsodium, budesonide, formoterol fumarate, triamcinolone acetonide,levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate,levalbuterol HCl, flunisolide, ceftriaxone sodium, amoxicillintrihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate,flunisolide/menthol, chlorpheniramine/hydrocodone, metaproterenolsulfate, methylprednisolone, mometasone furoate,p-ephedrine/cod/chlorphenir, pirbuterol acetate, p-ephedrine/loratadine,terbutaline sulfate, tiotropium bromide, (R,R)-formoterol, TgAAT,cilomilast and roflumilast.

Non-limiting examples of therapeutic agents for HCV with which acompound of Formula (I) can be combined include the following:Interferon-alpha-2α, Interferon-alpha-2β, Interferon-alpha con1,Interferon-alpha-n1, pegylated interferon-alpha-2α, pegylatedinterferon-alpha-2β, ribavirin, peginterferon alfa-2b+ribavirin,ursodeoxycholic acid, glycyrrhizic acid, thymalfasin, Maxamine, VX-497and any compounds that are used to treat HCV through intervention withthe following targets: HCV polymerase, HCV protease, HCV helicase, andHCV IRES (internal ribosome entry site).

Non-limiting examples of therapeutic agents for Idiopathic PulmonaryFibrosis with which a compound of Formula (I) can be combined includethe following: prednisone, azathioprine, albuterol, colchicine,albuterol sulfate, digoxin, gamma interferon, methylprednisolone sodiumsuccinate, lorazepam, furosemide, lisinopril, nitroglycerin,spironolactone, cyclophosphamide, ipratropium bromide, actinomycin d,alteplase, fluticasone propionate, levofloxacin, metaproterenol sulfate,morphine sulfate, oxycodone HCl, potassium chloride, triamcinoloneacetonide, tacrolimus anhydrous, calcium, interferon-alpha,methotrexate, mycophenolate mofetil and interferon-gamma-1β.

Non-limiting examples of therapeutic agents for myocardial infarctionwith which a compound of Formula (I) can be combined include thefollowing: aspirin, nitroglycerin, metoprolol tartrate, enoxaparinsodium, heparin sodium, clopidogrel bisulfate, carvedilol, atenolol,morphine sulfate, metoprolol succinate, warfarin sodium, lisinopril,isosorbide mononitrate, digoxin, furosemide, simvastatin, ramipril,tenecteplase, enalapril maleate, torsemide, retavase, losartanpotassium, quinapril hydrochloride/magnesium carbonate, bumetanide,alteplase, enalaprilat, amiodarone hydrochloride, tirofiban HClm-hydrate, diltiazem hydrochloride, captopril, irbesartan, valsartan,propranolol hydrochloride, fosinopril sodium, lidocaine hydrochloride,eptifibatide, cefazolin sodium, atropine sulfate, aminocaproic acid,spironolactone, interferon, sotalol hydrochloride, potassium chloride,docusate sodium, dobutamine HCl, alprazolam, pravastatin sodium,atorvastatin calcium, midazolam hydrochloride, meperidine hydrochloride,isosorbide dinitrate, epinephrine, dopamine hydrochloride, bivalirudin,rosuvastatin, ezetimibe/simvastatin, avasimibe, and cariporide.

Non-limiting examples of therapeutic agents for psoriasis with which acompound of Formula (I) can be combined include the following:calcipotriene, clobetasol propionate, triamcinolone acetonide,halobetasol propionate, tazarotene, methotrexate, fluocinonide,betamethasone diprop augmented, fluocinolone acetonide, acitretin, tarshampoo, betamethasone valerate, mometasone furoate, ketoconazole,pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea,betamethasone, clobetasol propionate/emoll, fluticasone propionate,azithromycin, hydrocortisone, moisturizing formula, folic acid,desonide, pimecrolimus, coal tar, diflorasone diacetate, etanerceptfolate, lactic acid, methoxsalen, hc/bismuth subgal/znox/resor,methylprednisolone acetate, prednisone, sunscreen, halcinonide,salicylic acid, anthralin, clocortolone pivalate, coal extract, coaltar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone,diazepam, emollient, fluocinonide/emollient, mineral oil/castor oil/nalact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen,salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib,infliximab, cyclosporine, alefacept, efalizumab, tacrolimus,pimecrolimus, PUVA, UWB, sulfasalazine, ABT-874 and ustekinamab.

Non-limiting examples of therapeutic agents for psoriatic arthritis withwhich a compound of Formula (I) can be combined include the following:methotrexate, etanercept, rofecoxib, celecoxib, folic acid,sulfasalazine, naproxen, leflunomide, methylprednisolone acetate,indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,betamethasone diprop augmented, infliximab, methotrexate, folate,triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenacsodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodiumthiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium,sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (U.S. Pat. No.6,090,382, HUMIRA™), and efalizumab.

Non-limiting examples of therapeutic agents for restenosis with which acompound of Formula (I) can be combined include the following:sirolimus, paclitaxel, everolimus, tacrolimus, ABT-578, andacetaminophen.

Non-limiting examples of therapeutic agents for sciatica with which acompound of Formula (I) can be combined include the following:hydrocodone bitartrate/apap, rofecoxib, cyclobenzaprine HCl,methylprednisolone, naproxen, ibuprofen, oxycodone HCl/acetaminophen,celecoxib, valdecoxib, methylprednisolone acetate, prednisone, codeinephosphate/apap, tramadol hcl/acetaminophen, metaxalone, meloxicam,methocarbamol, lidocaine hydrochloride, diclofenac sodium, gabapentin,dexamethasone, carisoprodol, ketorolac tromethamine, indomethacin,acetaminophen, diazepam, nabumetone, oxycodone HCl, tizanidine HCl,diclofenac sodium/misoprostol, propoxyphene n-pap, asa/oxycod/oxycodoneter, ibuprofen/hydrocodone bit, tramadol HCl, etodolac, propoxypheneHCl, amitriptyline HCl, carisoprodol/codeine phos/asa, morphine sulfate,multivitamins, naproxen sodium, orphenadrine citrate, and temazepam.

Preferred examples of therapeutic agents for SLE (Lupus) with which acompound of Formula (I) can be combined include the following: NSAIDS,for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin;COX2 inhibitors, for example, celecoxib, rofecoxib, valdecoxib;anti-malarials, for example, hydroxychloroquine; steroids, for example,prednisone, prednisolone, budenoside, dexamethasone; cytotoxics, forexample, azathioprine, cyclophosphamide, mycophenolate mofetil,methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, forexample Cellcept®. A compound of Formula (I) may also be combined withagents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran®and agents which interfere with synthesis, production or action ofproinflammatory cytokines such as IL-1, for example, caspase inhibitorslike IL-1β converting enzyme inhibitors and IL-Ira. A compound ofFormula (I) may also be used with T cell signaling inhibitors, forexample, tyrosine kinase inhibitors; or molecules that target T cellactivation molecules, for example, CTLA-4-IgG or anti-B7 familyantibodies, anti-PD-1 family antibodies. A compound of Formula (I) canbe combined with IL-11 or anti-cytokine antibodies, for example,fonotolizumab (anti-IFNg antibody), or anti-receptor receptorantibodies, for example, anti-IL-6 receptor antibody and antibodies toB-cell surface molecules. A compound of Formula (I) may also be usedwith LJP 394 (abetimus), agents that deplete or inactivate B-cells, forexample, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlySantibody), TNF antagonists, for example, anti-TNF antibodies, D2E7 (U.S.Pat. No. 6,090,382; HUMIRA™), CA2 (REMICADE™), CDP 571, TNFR-Igconstructs, (p75TNFRIgG (ENBREL™) and p55TNFRIgG (LENERCEPT™).

In this invention, the following definitions are applicable:

A “therapeutically effective amount” is an amount of a compound ofFormula (I) or a combination of two or more such compounds, whichinhibits, totally or partially, the progression of the condition oralleviates, at least partially, one or more symptoms of the condition. Atherapeutically effective amount can also be an amount which isprophylactically effective. The amount which is therapeuticallyeffective will depend upon the patient's size and gender, the conditionto be treated, the severity of the condition and the result sought. Fora given patient, a therapeutically effective amount can be determined bymethods known to those of skill in the art.

“Pharmaceutically acceptable salts” refers to those salts which retainthe biological effectiveness and properties of the free bases and whichare obtained by reaction with inorganic acids, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acidor organic acids such as sulfonic acid, carboxylic acid, organicphosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinicacid, benzoic acid, salicylic acid, lactic acid, tartaric acid (e.g. (+)or (−)-tartaric acid or mixtures thereof), amino acids (e.g. (+) or(−)-amino acids or mixtures thereof), and the like. These salts can beprepared by methods known to those skilled in the art.

Certain compounds of Formula (I) which have acidic substituents mayexist as salts with pharmaceutically acceptable bases. The presentinvention includes such salts. Examples of such salts include sodiumsalts, potassium salts, lysine salts and arginine salts. These salts maybe prepared by methods known to those skilled in the art.

Certain compounds of Formula (I) and their salts may exist in more thanone crystal form and the present invention includes each crystal formand mixtures thereof.

Certain compounds of Formula (I) and their salts may also exist in theform of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

Certain compounds of Formula (I) may contain one or more chiral centers,and exist in different optically active forms. When compounds of Formula(I) contain one chiral center, the compounds exist in two enantiomericforms and the present invention includes both enantiomers and mixturesof enantiomers, such as racemic mixtures. The enantiomers may beresolved by methods known to those skilled in the art, for example byformation of diastereoisomeric salts which may be separated, forexample, by crystallization; formation of diastereoisomeric derivativesor complexes which may be separated, for example, by crystallization,gas-liquid or liquid chromatography; selective reaction of oneenantiomer with an enantiomer-specific reagent, for example enzymaticesterification; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support for example silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where the desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step is required to liberate the desired enantiomeric form.Alternatively, specific enantiomers may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting one enantiomer into the other by asymmetrictransformation.

When a compound of Formula (I) contains more than one chiral center, itmay exist in diastereoisomeric forms. The diastereoisomeric compoundsmay be separated by methods known to those skilled in the art, forexample chromatography or crystallization and the individual enantiomersmay be separated as described above. The present invention includes eachdiastereoisomer of compounds of Formula (I), and mixtures thereof.

Certain compounds of Formula (I) may exist in different tautomeric formsor as different geometric isomers, and the present invention includeseach tautomer and/or geometric isomer of compounds of Formula (I) andmixtures thereof.

Certain compounds of Formula (I) may exist in different stableconformational forms which may be separable. Torsional asymmetry due torestricted rotation about an asymmetric single bond, for example becauseof steric hindrance or ring strain, may permit separation of differentconformers. The present invention includes each conformational isomer ofcompounds of Formula (I) and mixtures thereof.

Certain compounds of Formula (I) may exist in zwitterionic form and thepresent invention includes each zwitterionic form of compounds ofFormula (I) and mixtures thereof.

As used herein the term “pro-drug” refers to an agent which is convertedinto the parent drug in vivo by some physiological chemical process(e.g., a prodrug on being brought to the physiological pH is convertedto the desired drug form). Pro-drugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent drug is not. The pro-drug may also have improved solubility inpharmacological compositions over the parent drug. An example, withoutlimitation, of a pro-drug would be a compound of the present inventionwherein it is administered as an ester (the “pro-drug”) to facilitatetransmittal across a cell membrane where water solubility is notbeneficial, but then it is metabolically hydrolyzed to the carboxylicacid once inside the cell where water solubility is beneficial.

Pro-drugs have many useful properties. For example, a pro-drug may bemore water soluble than the ultimate drug, thereby facilitatingintravenous administration of the drug. A pro-drug may also have ahigher level of oral bioavailability than the ultimate drug. Afteradministration, the prodrug is enzymatically or chemically cleaved todeliver the ultimate drug in the blood or tissue.

Exemplary pro-drugs upon cleavage release the corresponding free acid,and such hydrolyzable ester-forming residues of the compounds of thisinvention include but are not limited to carboxylic acid substituentswherein the free hydrogen is replaced by (C₁-C₄)alkyl,(C₁-C₁₂)alkanoyloxymethyl, (C₄-C₉)1-(alkanoyloxy)ethyl,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)-alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Other exemplary pro-drugs release an alcohol of Formula (I) wherein thefree hydrogen of the hydroxyl substituent (e.g., R¹ contains hydroxyl)is replaced by (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₁₂)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylamino-methyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylactyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl wherein said α-aminoacyl moieties areindependently any of the naturally occurring L-amino acids found inproteins, P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radicalresulting from detachment of the hydroxyl of the hemiacetal of acarbohydrate).

As used herein, the term “bridged (C₅-C₁₂) cycloalkyl group” means asaturated or unsaturated, bicyclic or polycyclic bridged hydrocarbongroup having two or three C₃-C₁₀ cycloalkyl rings. Non bridgedcycloalkyls are excluded. Bridged cyclic hydrocarbon may include, suchas bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, bicyclo[4.3.1]decyl, bicyclo[3.3.1]nonyl, bornyl,bornenyl, norbornyl, norbornenyl, 6,6-dimethylbicyclo[3.1.1]heptyl,tricyclobutyl, and adamantyl.

As used herein the term “bridged (C₂-C₁₀) heterocyclyl” means bicyclicor polycyclic aza-bridged hydrocarbon groups and may includeazanorbornyl, quinuclidinyl, isoquinuclidinyl, tropanyl,azabicyclo[3.2.1]octanyl, azabicyclo[2.2.1]heptany1,2-azabicyclo[3.2.1]octanyl, azabicyclo[3.2.1]octanyl,azabicyclo[3.2.2]nonanyl, azabicyclo[3.3.0]nonanyl, andazabicyclo[3.3.1]nonanyl.

The term “heterocyclic”, “heterocyclyl” or “heterocyclylene”, as usedherein, include non-aromatic, ring systems, including, but not limitedto, monocyclic, bicyclic, tricyclic and spirocyclic rings, which can becompletely saturated or which can contain one or more units ofunsaturation, for the avoidance of doubt, the degree of unsaturationdoes not result in an aromatic ring system) and have 5 to 12 atomsincluding at least one heteroatom, such as nitrogen, oxygen, or sulfur.For purposes of exemplification, which should not be construed aslimiting the scope of this invention, the following are examples ofheterocyclic rings: azepinyl, azetidinyl, indolinyl, isoindolinyl,morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinucludinyl,thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl,tetrahydroindolyl, thiomorpholinyl and tropanyl.

The term “heteroaryl” or “heteroarylene” as used herein, includearomatic ring systems, including, but not limited to, monocyclic,bicyclic and tricyclic rings, and have 5 to 12 atoms including at leastone heteroatom, such as nitrogen, oxygen, or sulfur. For purposes ofexemplification, which should not be construed as limiting the scope ofthis invention: azaindolyl, benzo[b]thienyl, benzimidazolyl,benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl,indazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, purinyl,pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl,pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl,quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrazolyl,thiadiazolyl, or thienyl.

An “heterocycloalkyl” group, as used herein, is a heterocyclic groupthat is linked to a compound by an aliphatic group having from one toabout eight carbon atoms. For example, a heterocycloalkyl group is amorpholinomethyl group.

As used herein, “alkyl”, “alkylene” or notations such as “(C₁-C₈)”include straight chained or branched hydrocarbons which are completelysaturated. Examples of alkyls are methyl, ethyl, propyl, isopropyl,butyl, pentyl, hexyl and isomers thereof. As used herein, “alkenyl”,“alkenylene”, “alkynylene” and “alkynyl” means C₂-C₈ and includesstraight chained or branched hydrocarbons which contain one or moreunits of unsaturation, one or more double bonds for alkenyl and one ormore triple bonds for alkynyl.

As used herein, “aromatic” groups (or “aryl” or “arylene” groups)include aromatic carbocyclic ring systems (e.g. phenyl) and fusedpolycyclic aromatic ring systems (e.g. naphthyl, biphenyl and1,2,3,4-tetrahydronaphthyl).

As used herein, “cycloalkyl” or “cycloalkylene” means C₃-C₁₂ monocyclicor multicyclic (e.g., bicyclic, tricyclic, spirocyclic, etc.)hydrocarbons that is completely saturated or has one or more unsaturatedbonds but does not amount to an aromatic group. Examples of a cycloalkylgroup are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl and cyclohexenyl.

As used herein, many moieties or substituents are termed as being either“substituted” or “optionally substituted”. When a moiety is modified byone of these terms, unless otherwise noted, it denotes that any portionof the moiety that is known to one skilled in the art as being availablefor substitution can be substituted, which includes one or moresubstituents, where if more than one substituent then each substituentis independently selected. Such means for substitution are well-known inthe art and/or taught by the instant disclosure. For purposes ofexemplification, which should not be construed as limiting the scope ofthis invention, some examples of groups that are substituents are:(C₁-C₈)alkyl groups, (C₂-C₈)alkenyl groups, (C₂-C₈)alkynyl groups,(C₃-C₁₀)cycloalkyl groups, halogen (F, Cl, Br or I), halogenated(C₁-C₈)alkyl groups (for example but not limited to —CF₃),—O—(C₁-C₈)alkyl groups, —OH, —S—(C₁-C₈)alkyl groups, —SH,—NH(C₁-C₈)alkyl groups, —N((C₁-C₈)alkyl)₂ groups, —NH₂, —C(O)NH₂,—C(O)NH(C₁-C₈)alkyl groups, —C(O)N((C₁-C₈)alkyl)₂, —NHC(O)H, —NHC(O)(C₁-C₈)alkyl groups, —NHC(O) (C₃-C₈)cycloalkyl groups,—N((C₁-C₈)alkyl)C(O)H, —N((C₁-C₈)alkyl)C(O)(C₁-C₈)alkyl groups,—NHC(O)NH₂, —NHC(O)NH(C₁-C₈)alkyl groups, —N((C₁-C₈)alkyl)C(O)NH₂groups, —NHC(O)N((C₁-C₈)alkyl)₂ groups,—N((C₁-C₈)alkyl)C(O)N((C₁-C₈)alkyl)₂ groups,—N((C₁-C₈)alkyl)C(O)NH((C₁-C₈)alkyl), —C(O)H, —C(O)(C₁-C₈)alkyl groups,—CN, —NO₂, —S(O)(C₁-C₈)alkyl groups, —S(O)₂(C₁-C₈)alkyl groups,—S(O)₂N((C₁-C₈)alkyl)₂ groups, —S(O)₂NH(C₁-C₈)alkyl groups,—S(O)₂NH(C₃-C₈)cycloalkyl groups, —S(O)₂NH₂ groups, —NHS(O)₂(C₁-C₈)alkylgroups, —N((C₁-C₈)alkyl)S(O)₂(C₁-C₈)alkyl groups,—(C₁-C₈)alkyl-O—(C₁-C₈)alkyl groups, —O—(C₁-C₈)alkyl-O—(C₁-C₈)alkylgroups, —C(O)OH, —C(O)O(C₁-C₈)alkyl groups, NHOH, NHO(C₁-C₈)alkylgroups, —O-halogenated (C₁-C₈)alkyl groups (for example but not limitedto —OCF₃), —S(O)₂-halogenated (C₁-C₈)alkyl groups (for example but notlimited to —S(O)₂CF₃), —S-halogenated (C₁-C₈)alkyl groups (for examplebut not limited to —SCF₃), —(C₁-C₆) heterocycle (for example but notlimited to pyrrolidine, tetrahydrofuran, pyran or morpholine), —(C₁-C₆)heteroaryl (for example but not limited to tetrazole, imidazole, furan,pyrazine or pyrazole), -phenyl, —NHC(O)O—(C₁-C₆)alkyl groups,—N((C₁-C₆)alkyl)C(O)O—(C₁-C₆)alkyl groups, —C(═NH)—(C₁-C₆)alkyl groups,—C(═NOH)—(C₁-C₆)alkyl groups, or —C(═N—O—(C₁-C₆)alkyl)-(C₁-C₆)alkylgroups.

in Formula (I) represents an aromatic ring.

One or more compounds of this invention can be administered to a humanpatient by themselves or in pharmaceutical compositions where they aremixed with biologically suitable carriers or excipient(s) at doses totreat or ameliorate a disease or condition as described herein. Mixturesof these compounds can also be administered to the patient as a simplemixture or in suitable formulated pharmaceutical compositions. Atherapeutically effective dose refers to that amount of the compound orcompounds sufficient to result in the prevention or attenuation of adisease or condition as described herein. Techniques for formulation andadministration of the compounds of the instant application may be foundin references well known to one of ordinary skill in the art, such as“Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa.,latest edition.

Suitable routes of administration may, for example, include oral,eyedrop, rectal, transmucosal, topical, or intestinal administration;parenteral delivery, including intramuscular, subcutaneous,intramedullary injections, as well as intrathecal, directintraventricular, intravenous, intraperitoneal, intranasal, orintraocular injections.

Alternatively, one may administer the compound in a local rather than asystemic manner, for example, via injection of the compound directlyinto an edematous site, often in a depot or sustained releaseformulation.

Furthermore, one may administer the drug in a targeted drug deliverysystem, for example, in a liposome coated with endothelial cell-specificantibody.

The pharmaceutical compositions of the present invention may bemanufactured in a manner that is itself known, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the presentinvention thus may be formulated in a conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For injection, the agents of the invention may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks' solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants appropriate to the barrier to bepermeated are used in the formulation. Such penetrants are generallyknown in the art.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by combining the active compound with a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired,disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds can be formulated for parenteral administration byinjection, e.g. bolus injection or continuous infusion. Formulations forinjection may be presented in unit dosage form, e.g. in ampoules or inmulti-dose containers, with an added preservative. The compositions maytake such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly or by intramuscular injection). Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

An example of a pharmaceutical carrier for the hydrophobic compounds ofthe invention is a cosolvent system comprising benzyl alcohol, anonpolar surfactant, a water-miscible organic polymer, and an aqueousphase. The cosolvent system may be the VPD co-solvent system. VPD is asolution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactantpolysorbate 80, and 65% w/v polyethylene glycol 300, made up to volumein absolute ethanol. The VPD co-solvent system (VPD:5W) consists of VPDdiluted 1:1 with a 5% dextrose in water solution. This co-solvent systemdissolves hydrophobic compounds well, and itself produces low toxicityupon systemic administration. Naturally, the proportions of a co-solventsystem may be varied considerably without destroying its solubility andtoxicity characteristics. Furthermore, the identity of the co-solventcomponents may be varied: for example, other low-toxicity nonpolarsurfactants may be used instead of polysorbate 80; the fraction size ofpolyethylene glycol may be varied; other biocompatible polymers mayreplace polyethylene glycol, e.g. polyvinyl pyrrolidone; and othersugars or polysaccharides may substitute for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. Certainorganic solvents such as dimethysulfoxide also may be employed, althoughusually at the cost of greater toxicity. Additionally, the compounds maybe delivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials have been established and are wellknown by those skilled in the art. Sustained-release capsules may,depending on their chemical nature, release the compounds for a fewweeks up to over 100 days. Depending on the chemical nature and thebiological stability of the therapeutic reagent, additional strategiesfor protein stabilization may be employed.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

Many of the compounds of the invention may be provided as salts withpharmaceutically compatible counterions. Pharmaceutically compatiblesalts may be formed with many acids, including but not limited tohydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.Salts tend to be more soluble in aqueous or other protonic solvents thanare the corresponding free base forms.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in aneffective amount to achieve its intended purpose. More specifically, atherapeutically effective amount means an amount effective to preventdevelopment of or to alleviate the existing symptoms of the subjectbeing treated. Determination of the effective amounts is well within thecapability of those skilled in the art.

For any compound used in a method of the present invention, thetherapeutically effective dose can be estimated initially from cellularassays. For example, a dose can be formulated in cellular and animalmodels to achieve a circulating concentration range that includes theIC₅₀ as determined in cellular assays (i.e., the concentration of thetest compound which achieves a half-maximal inhibition of a givenprotein kinase activity). In some cases it is appropriate to determinethe IC₅₀ in the presence of 3 to 5% serum albumin since such adetermination approximates the binding effects of plasma protein on thecompound. Such information can be used to more accurately determineuseful doses in humans. Further, the most preferred compounds forsystemic administration effectively inhibit protein kinase signaling inintact cells at levels that are safely achievable in plasma.

A therapeutically effective dose refers to that amount of the compoundthat results in amelioration of symptoms in a patient. Toxicity andtherapeutic efficacy of such compounds can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the maximum tolerated dose (MTD) and the ED₅₀(effective dose for 50% maximal response). The dose ratio between toxicand therapeutic effects is the therapeutic index and it can be expressedas the ratio between MTD and ED₅₀. Compounds which exhibit hightherapeutic indices are preferred. The data obtained from these cellculture assays and animal studies can be used in formulating a range ofdosage for use in humans. The dosage of such compounds lies preferablywithin a range of circulating concentrations that include the ED₅₀ withlittle or no toxicity. The dosage may vary within this range dependingupon the dosage form employed and the route of administration utilized.The exact formulation, route of administration and dosage can be chosenby the individual physician in view of the patient's condition (see e.g.Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch.1 p. 1). In the treatment of crises, the administration of an acutebolus or an infusion approaching the MTD may be required to obtain arapid response.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain thekinase modulating effects, or minimal effective concentration (MEC). TheMEC will vary for each compound but can be estimated from in vitro data;e.g. the concentration necessary to achieve 50-90% inhibition of proteinkinase using the assays described herein. Dosages necessary to achievethe MEC will depend on individual characteristics and route ofadministration. However, HPLC assays or bioassays can be used todetermine plasma concentrations.

Dosage intervals can also be determined using the MEC value. Compoundsshould be administered using a regimen which maintains plasma levelsabove the MEC for 10-90% of the time, preferably between 30-90% and mostpreferably between 50-90% until the desired amelioration of symptoms isachieved. In cases of local administration or selective uptake, theeffective local concentration of the drug may not be related to plasmaconcentration.

The amount of composition administered will, of course, be dependent onthe subject being treated, on the subject's weight, the severity of theaffliction, the manner of administration and the judgment of theprescribing physician.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. Compositions comprisinga compound of the invention formulated in a compatible pharmaceuticalcarrier may also be prepared, placed in an appropriate container, andlabelled for treatment of an indicated condition.

In some formulations it may be beneficial to use the compounds of thepresent invention in the form of particles of very small size, forexample as obtained by fluid energy milling.

The use of compounds of the present invention in the manufacture ofpharmaceutical compositions is illustrated by the following description.In this description the term “active compound” denotes any compound ofthe invention but particularly any compound which is the final productof one of the following Examples.

a) Capsules

In the preparation of capsules, 10 parts by weight of active compoundand 240 parts by weight of lactose can be de-aggregated and blended. Themixture can be filled into hard gelatin capsules, each capsulecontaining a unit dose or part of a unit dose of active compound.

b) Tablets

Tablets can be prepared, for example, from the following ingredients.

Parts by weight Active compound 10 Lactose 190 Maize starch 22Polyvinylpyrrolidone 10 Magnesium stearate 3

The active compound, the lactose and some of the starch can bede-aggregated, blended and the resulting mixture can be granulated witha solution of the polyvinylpyrrolidone in ethanol. The dry granulate canbe blended with the magnesium stearate and the rest of the starch. Themixture is then compressed in a tabletting machine to give tablets eachcontaining a unit dose or a part of a unit dose of active compound.

c) Enteric Coated Tablets

Tablets can be prepared by the method described in (b) above. Thetablets can be enteric coated in a conventional manner using a solutionof 20% cellulose acetate phthalate and 3% diethyl phthalate inethanol:dichloromethane (1:1).

d) Suppositories

In the preparation of suppositories, for example, 100 parts by weight ofactive compound can be incorporated in 1300 parts by weight oftriglyceride suppository base and the mixture formed into suppositorieseach containing a therapeutically effective amount of active ingredient.

In the compositions of the present invention the active compound may, ifdesired, be associated with other compatible pharmacologically activeingredients. For example, the compounds of this invention can beadministered in combination with another therapeutic agent that is knownto treat a disease or condition described herein. For example, with oneor more additional pharmaceutical agents that inhibit or prevent theproduction of VEGF or angiopoietins, attenuate intracellular responsesto VEGF or angiopoietins, block intracellular signal transduction,inhibit vascular hyperpermeability, reduce inflammation, or inhibit orprevent the formation of edema or neovascularization. The compounds ofthe invention can be administered prior to, subsequent to orsimultaneously with the additional pharmaceutical agent, whichevercourse of administration is appropriate. The additional pharmaceuticalagents include, but are not limited to, anti-edemic steroids, NSAIDS,ras inhibitors, anti-TNF agents, anti-IL1 agents, antihistamines,PAF-antagonists, COX-1 inhibitors, COX-2 inhibitors, NO synthaseinhibitors, Akt/PTB inhibitors, IGF-1R inhibitors, PKC inhibitors, P13kinase inhibitors, calcineurin inhibitors and immunosuppressants. Thecompounds of the invention and the additional pharmaceutical agents acteither additively or synergistically. Thus, the administration of such acombination of substances that inhibit angiogenesis, vascularhyperpermeability and/or inhibit the formation of edema can providegreater relief from the deletrious effects of a hyperproliferativedisorder, angiogenesis, vascular hyperpermeability or edema than theadministration of either substance alone. In the treatment of malignantdisorders combinations with antiproliferative or cytotoxicchemotherapies or radiation are included in the scope of the presentinvention.

The present invention also comprises the use of a compound of Formula(I) as a medicament.

A further aspect of the present invention provides the use of a compoundof Formula (I) or a salt thereof in the manufacture of a medicament fortreating vascular hyperpermeability, angiogenesis-dependent disorders,proliferative diseases and/or disorders of the immune system in mammals,particularly human beings.

The present invention also provides a method of treating vascularhyperpermeability, inappropriate neovascularization, proliferativediseases and/or disorders of the immune system which comprises theadministration of a therapeutically effective amount of a compound ofFormula (I) to a mammal, particularly a human being, in need thereof.

Abbreviations

-   aa Amino acids-   AcOH Glacial acetic acid-   ATP Adenosine triphosphate-   Boc t-Butoxycarbonyl-   t-BuOH tert-Butanol-   BOP-CL Bis(2-oxo-3-oxazolidinyl)phosphinic chloride-   BSA Bovine serum albumin-   BuOH Butanol-   Cbz Carboxybenzyl-   CDI 1,1′-Carbonyldiimidazole-   CT Computed tomography-   CyPFt-Bu    1-Dicyclohexylphosphino-2-di-tert-butylphosphinoethylferrocene-   d Doublet-   dba Dibenzylideneacetone-   DCC Dicyclohexylcarbodiimide-   DCE Dichloroethane-   DCM Dichloromethane (methylene chloride)-   dd Doublet of doublets-   DIBAL-H Diisobutylaluminium hydride-   DIEA N,N-Diisopropylethylamine-   DMA Dimethylacetamide-   DMAP N,N-Dimethylaminopyridine-   DME 1,2-Dimethoxyethane-   DMEM Dulbecco's Modified Eagle Medium-   DMF N,N-Dimethylformamide-   DMSO Dimethyl sulfoxide-   DNP-HSA Dinitrophenyl-human serum albumin-   DTT Dithiothreitol-   dppf 1,1′-Bis(diphenylphosphino)ferrocene-   EDC.HCl N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA Ethylene diamine tetraacetic acid-   equiv Equivalent(s)-   Et₂NH Diethylamine-   EtOAc Ethyl acetate-   Et₂O Diethyl ether-   EtOH Ethanol-   FBS Fetal bovine serum-   FLAG DYKDDDDK peptide sequence-   g Gram(s)-   GST Glutathione S-transferase-   h Hour(s)-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES N-2-Hydroxyethylpiperazine-N′-2-ethanesulfonic acid-   HOBt Hydroxybenzotriazole-   HPLC High-pressure liquid chromatography-   IBCF Isobutylchloroformate-   i.d. Intradermal-   IFA Incomplete Freunds Adjuvant-   IPA Isopropyl alcohol-   LC/MS Liquid chromatography/mass spectrometry-   LDA Lithium diisopropylamide-   LHMDS Lithium bis(trimethylsilyl)amide-   m Multiplet-   M Molar-   MeCN Acetonitrile-   MeOH Methyl alcohol-   min Minute(s)-   mmol Millimole-   MOPS 3-(N-morpholino)-2-hydroxypropanesulfonic acid-   MOPSO 3-(N-morpholino)-propanesulfonic acid-   MS Mass spectrometry-   n-Normal (nonbranched)-   N Normal-   NaOt-Bu Sodium tert-butoxide-   NH₄OAc Ammonium acetate-   NMM N-Methylmorpholine-   NMP N-methylpyrrolidinone-   NMR Nuclear magnetic resonance-   OD Optical density-   or Optical rotation-   PBS Phosphate buffered saline-   pH −log [H⁺]-   pNAG Nitrophenyl-N-acetyl-β-D-glucosaminide-   ppm Parts per million-   PrOH Propanol-   psi Pounds per square inch-   ref Relative centrifugal force-   RP-HPLC Reverse-phase high-pressure liquid chromatography-   R_(t) Retention time-   rt Room temperature-   s Singlet-   SEM 2-(Trimethylsilyl)ethoxymethyl-   SLM Standard liters per minute-   t Triplet-   t-Tertiary-   TBAF Tetra-n-Butylammonium fluoride-   TEA Triethylamine-   tert-Tertiary-   TFA Trifluoroacetate-   TFAA Trifluoracetic anhydride-   THF Tetrahydrofuran-   TIPS Triisopropylsilyl-   TLC Thin layer chromatography-   TMS Trimethylsilyl-   USP United States Pharmacopeia-   UW Ultraviolet-   wt % Weight percent

Assays

In Vitro Jak1 Kinase Activity Measured by Homogenous Time-ResolvedFluorescence (HTRF)

Purified Jak1 enzyme (aa 845-1142; expressed in SF9 cells as a GSTfusion and purified by glutathione affinity chromatography) was mixedwith 2 μM peptide substrate (biotin-TYR2, Sequence:Biotin-(Ahx)-AEEEYFFLFA-amide) at varying concentrations of inhibitor inreaction buffer: 50 mM MOPSO pH 6.5, 10 mM MgCl₂, 2 mM MnCl₂, 2.5 mMDTT, 0.01% BSA, 0.1 mM Na₃VO₄ and 0.001 mM ATP. After about 60 minincubation at room temperature, the reaction was quenched by addition ofEDTA (final concentration: 100 mM) and developed by addition ofrevelation reagents (final approximate concentrations: 30 mM HEPES pH7.0, 0.06% BSA, 0.006% Tween-20, 0.24 M KF, 80 ng/mL PT66K (europiumlabeled anti-phosphotyrosine antibody cat #61T66KLB Cisbio, Bedford,Mass.) and 3.12 μg/mL SAXL (Phycolink streptavidin-allophycocyaninacceptor, cat #PJ52S, Prozyme, San Leandro, Calif.). The developedreaction was incubated in the dark either at about 4° C. for about 14 hor for about 60 min at room temperature, then read via a time-resolvedfluorescence detector (Rubystar, BMG) using a 337 nm laser forexcitation and emission wavelengths of 620 nm and 665 nm. Within thelinear range of the assay, the ratio of observed signal at 620 nm and665 nm is directly related to phosphorylated product and used tocalculate the IC₅₀ values.

Other kinase assays were performed using a similar protocol. Additionalpurified enzymes Tyk2 (aa 880-1185 with an N-terminal histidine-tag andC-terminal FLAG tag; purified in-house by immobilized metal ion affinitychromatography), RET (aa 711-1072 with an N-terminal histidine-tag;purified by immobilized metal ion affinity chromatography) and KDR (aa792-1354 with an N-terminal histidine-tag; purified in-house byimmobilized metal ion affinity and ion-exchange chromatography) wereexpressed in SF9 cells and Aurora 1/B (aa1-344 with a N-terminalhistidine-tag and purified by immobilized metal ion affinitychromatography) was expressed in E. coli. Other enzymes used areavailable from commercial sources. Enzymes were mixed with biotinylatedsubstrates at varying concentrations of inhibitor in different reactionbuffers (see Table 1). After about 60 min incubation at roomtemperature, the reaction was quenched by addition of EDTA and developedby addition of revelation reagents (final approximate concentrations: 30mM HEPES pH 7.0, 0.06% BSA, 0.006% Tween-20, 0.24 M KF, varying amountsof donor europium labeled antibodies and acceptor streptavidin labeledallophycocyanin (SAXL)). The developed reactions were incubated in thedark at about 4° C. for about 14 h or for about 60 min at roomtemperature, then read in a time-resolved fluorescence detector(Rubystar, BMG Labtech) as described above.

TABLE 1 Specific conditions (per 40 μL enzyme reaction) for the variousenzymes are detailed below: Enzyme ATP DMSO Reaction Assay Conc.Substrate Conc. Conc. Time Detection Enzyme Construct Substrate Buffer(ng/well) Conc. (mM) (%) (min) condition Jak1 aa 845- Biotin- MOPSO 5 2uM 0.001 5 60 8 ng/well 1142 TYR2 PT66K, 0.39 ug/well SAXL Jak2Millipore Biotin- MOPSO 2.5 2 uM 0.001 5 60 8 ng/well cat# 14-640 TYR1PT66K, 0.078 ug/well SAXL Jak3 Millipore Biotin- MOPSO 1 2 uM 0.001 5 608 ng/well cat# 14-629 TYR2 PT66K, 0.078 ug/well SAXL Tyk2 aa880-1185Biotin- MOPSO 9 2 uM 0.001 5 60 8 ng/well TYR1 PT66K, 0.078 ug/well SAXLAurora aa1-344 KinEASE MOPS 20 0.5 uM 0.1 5 60 15 ng/well 1/B S2 Eu-STK-Ab, 0.34 ug/wel SAXL KDR aa789-1354 Biotin- HEPES 10 2 uM 0.1 5 60 8ng/well TYR2 PT66K, 0.078 ug/well SAXL JNK1 Millipore Biotin- MOPS 10 1uM 0.01 5 60 2.58 cat# 14-327 ATF2- ng/well pep Anti- pATF2-Eu, 0.6ug/well SAXL JNK2 Millipore Biotin- MOPS 5 0.5 uM 0.01 5 60 2.58 cat#14-329 ATF2- ng/well pep Anti- pATF2-Eu, 0.6 ug/well SAXL RET aa711-1072Biotin- HEPES 4 10 ng/well 0.01 5 60 8 ng/well poly PT66K, GluTyr 0.078ug/well SAXL P70 S6 Millipore KinEASE MOPS 0.5 0.25 uM 0.01 5 60 15ng/well Kinase cat# 14-486 S3 Eu-STK- Ab, 0.34 ug/well SAXL PKN2Invitrogen KinEASE MOPS 0.7 0.5 uM 0.001 5 60 15 ng/well cat# S3 Eu-STK-PV3879 Ab, 0.34 ug/well SAXL Syk Millipore Biotin- MOPSO 3.8 4 uM 0.01 560 11.3 cat #14-314 TYR1 ng/well PT66K, 0.075 ug/well SAXL CDK2/Millipore Biotin- MOPS 50 2 uM 0.1 5 60 15 ng/well Cyclin A cat# 14-448MBP Anti- pMBP-Eu; 0.34 ug/well SAXLReaction Buffers:

MOPSO buffer contains: 50 mM MOPSO pH 6.5, 10 mM MgCl₂, 2 mM MnCl₂, 2.5mM DTT, 0.01% BSA, and 0.1 mM Na₃VO₄

HEPES buffer contains: 50 mM HEPES pH 7.1, 2.5 mM DTT, 10 mM MgCl₂, 2 mMMnCl₂, 0.01% BSA, and 0.1 mM Na₃VO₄

MOPS buffer contains: 20 mM MOPS pH 7.2, 10 mM MgCl₂, 5 mM EGTA, 5 mMBeta-phosphoglycerol, 1 mM Na₃VO₄, 0.01% Triton-X-100 and 1 mM DTT

Substrates:

-   Biotin-ATF2-peptide sequence: Biotin-(Ahx)-AGAGDQTPTPTRFLKRPR-amide-   Biotin-TYR1-peptide sequence: Biotin-(Ahx)-GAEEEIYAAFFA-COOH-   Biotin-TYR2-peptide sequence: Biotin-(Ahx)-AEEEYFFLFA-amide-   Biotin-MBP-peptide sequence:    Biotin-(Ahx)-VHFFKNIVTPRTPPPSQGKGAEGQR-amide-   Biotin-polyGluTyr peptide was purchased from Cisbio (cat #61 GTOBLA,    Bedford, Mass.)-   KinEASE S2 and S3 peptides were purchased from Cisbio (cat    #62STOPEB, Bedford, Mass.)    Detection Reagents:-   Anti-pATF2-Eu was custom-labeled by Cisbio (Bedford, Mass.)-   Anti-pMBP-Eu was custom-labeled by Cisbio (Bedford, Mass.)-   PT66K was purchased from Cisbio (cat #61T66KLB, Bedford, Mass.)-   SAXL was purchased from Prozyme (cat #PJ25S, San Leandro, Calif.)    In Vitro Syk Kinase Activity Measured by Homogenous Time-Resolved    Fluorescence (HTRF)

1 nM purified full-length Syk enzyme (purchased from Millipore,Billerica, Mass., Cat #14-314) was mixed with 0.1 μM peptide substrate(biotin-TYR1, Sequence: Biotin-(Ahx)-GAEEEIYAAFFA-COOH) at varyingconcentrations of inhibitor in reaction buffer: 50 mM MOPSO pH 6.5, 10mM MgCl₂, 2 mM MnCl₂, 2.5 mM DTT, 0.01% BSA, 0.1 mM Na₃VO₄ and 0.01 mMATP. After about 60 min incubation at room temperature, the reaction wasquenched by addition of EDTA (final concentration: 100 mM) and developedby addition of revelation reagents (final approximate concentrations: 30mM HEPES pH 7.0, 0.06% BSA, 0.006% Tween-20, 0.24 M KF, 90 ng/mL PT66K(europium labeled anti-phosphotyrosine antibody cat #61T66KLB Cisbio,Bedford, Mass.) and 0.6 μg/mL SAXL (Phycolinkstreptavidin-allophycocyanin acceptor, cat #PJ52S, Prozyme, San Leandro,Calif.). The developed reaction was incubated in the dark either atabout 4° C. for about 14 h or for about 60 min at room temperature, thenread via a time-resolved fluorescence detector (Rubystar, BMG) using a337 nm laser for excitation and emission wavelengths of 620 nm and 665nm. Within the linear range of the assay, the ratio of observed signalat 620 nm and 665 nm is directly related to phosphorylated product andused to calculate the IC₅₀ values.

Human T-Blasts IL-2 pSTAT5 Cellular Assay

Materials:

Phytohemaglutinin T-blasts were prepared from Leukopacks purchased fromBiological Specialty Corporation, Colmar, Pa. 18915, and cryopreservedin 5% DMSO/media prior to assay. For this assay the cells were thawed inassay medium with the following composition: RPMI 1640 medium (Gibco11875093) with 2 mM L-glutamine (Gibco 25030-081), 10 mM HEPES (Gibco15630-080), 100 μg/mL Pen/Strep (Gibco 15140-122), and 10% heatinactivated FBS (Gibco 10438026). Other materials used in the assay:DMSO (Sigma D2650), 96-well dilution plates (polypropylene) (Corning3365), 96-well assay plates (white, ½ area, 96 well) (Corning 3642),D-PBS (Gibco 14040133), IL-2 (R&D 202-IL-10 (10 μg)), Alphascreen pSTAT5kit (Perkin Elmer TGRS5S10K) and Alphascreen protein A kit (Perkin Elmer6760617M)

Methods:

T-Blasts were thawed and cultured for about 24 h without IL-2 prior toassay. Test compounds or controls are dissolved and serially diluted in100% DMSO. DMSO stocks are subsequently diluted 1:50 in cell culturemedia to create the 4× compound stocks (containing 2% DMSO). Using aCorning white 96 well, ½ area plate, cells are plated at 2×10⁵/10μl/well in 10 μL media followed by addition of 5 μL of 4× test compoundin duplicate. Cells are incubated with compound for about 0.5 h at about37° C. Next, 5 μL of IL-2 stock is added at 20 ng/mL finalconcentration. IL-2 is stored as a 4 μg/mL stock solution, as specifiedby the manufacturer, at about −20° C. in aliquots and diluted 1:50 withassay media (to 80 ng/mL) just prior to use. The contents of the wellsare mixed by carefully tapping sides of plate(s) several times followedby incubation at about 37° C. for about 15 min. The assay is terminatedby adding 5 μL of 5× AlphaScreen lysis buffer and shaking on an orbitalshaker for about 10 min at room temperature. Alphascreen acceptor beadmix is reconstituted following Perkin Elmer's protocol. 30 μL/well ofreconstituted Alphascreen acceptor bead mix was added, covered with foilthen shaken on orbital shaker for about 2 min on high then about 2 h onlow. Donor bead mix is reconstituted following Perkin Elmer'sAlphaScreen protocol; 12 μL/well are added, covered with foil thenshaken for about 2 min on high, and about 2 h on low. Plates are read onan EnVision reader following Perkin Elmer's AlphaScreen protocolinstructions.

TF-1 IL-6 pSTAT3 Cellular Assay

Materials:

TF-1 cells (ATCC #CRL-2003). Culture medium: DMEM medium (Gibco11960-044) with 2 mM L-glutamine (Gibco 25030-081), 10 mM HEPES (Gibco15630-080), 100 μg/mL Pen/Strep (Gibco 15140-122), 1.5 g/L sodiumbicarbonate (Gibco 25080-094), 1 mM sodium pyruvate (Gibco 11360-070),10% heat inactivated FBS (Gibco 10437-028), and 2 ng/mL GM-CSF (R&D215-GM-010). Other materials used in this assay: DMSO (Sigma D2650),96-well dilution plates (polypropylene) (Corning 3365), 96-well assayplates (white, ½ area, 96 well) (Corning 3642), D-PBS (Gibco 14040133),IL-6 (R&D 206-IL/CF-050 (50 μg)), Alphascreen pSTAT3 kit (Perkin ElmerTGRS3S10K) and Alphascreen protein A kit (Perkin Elmer 6760617M).

Methods:

Prior to the assay, cells are cultured for about 18 h in the culturemedium without GM-CSF. Test compounds or controls are dissolved andserially diluted in 100% DMSO. DMSO stocks are subsequently diluted 1:50in cell culture media to create the 4× compound stocks (containing 2%DMSO). Using a Corning white 96 well, ½ area plate, cells are plated at2×10⁷/10 μL/well in 10 μL media followed by addition of 5 μL of the 4×test compound stock in duplicate. Cells are incubated with compound forabout 0.5 h at about 37° C. followed by addition of 5 μL of 400 ng/mLIL-6. IL-6 is stored in 10 μg/mL aliquots using endotoxin free D-PBS(0.1% BSA) at about −20° C. Prior to assay IL-6 is diluted to 400 ng/mLin culture media and applied (5 μL/well) to all wells, except tonegative control wells where 5 μL/well of media is added. The contentsof the wells are mixed carefully by tapping the side of the plateseveral times. Plates are incubated at about 37° C. for about 30 min.Cells are lysed by adding 5 μL of 5× AlphaScreen cell lysis buffer toall wells, shaken for about 10 min at room temperature then assayed.Alternatively, assay plates may be frozen at about −80° C. and thawedlater at room temperature. Using the pSTAT3 SureFire Assay kit (PerkinElmer #TGRS3S10K) acceptor bead mix is reconstituted following PerkinElmer's AlphaScreen protocol instructions. 30 μL are added per well thenthe plate is covered with foil and shaken on an orbital shaker for about2 min on high, then about 2 h on low at room temperature. Donor bead mixis reconstituted following Perkin Elmer's AlphaScreen protocolinstructions. 12 μL are added per well, then covered with foil andshaken on orbital shaker for about 2 min on high, then about 2 h on lowat about 37° C. Plates are read on an EnVision reader following PerkinElmer's AlphaScreen protocol instructions at room temperature.

UT7/EPO pSTAT5 Cellular Assay

Materials:

UT7/EPO cells are passaged with erythropoietin (EPO), split twice perweek and fresh culture medium is thawed and added at time of split.Culture Medium: DMEM medium (Gibco 11960-044) with 2 mM L-glutamine(Gibco 25030-081), 10 mM HEPES (Gibco 15630-080), 100 U/mL Pen/Strep(Gibco 15140-122), 10% heat inactivated FBS (Gibco 10437-028), EPO (5μL/mL=7.1 μL of a 7 μg/mL stock per mL of medium). Assay media: DMEM, 2mM L-glutamine, 5% FBS, 10 mM HEPES. Other materials used in the assay:DMSO (Sigma D2650), 96-well dilution plates (polypropylene) (Corning3365), 96-well assay plates (white, 12 area, 96 well) (Corning 3642),D-PBS (Gibco 14040133), IL-2 (R&D 202-IL-10 (10 μg)), Alphascreen pSTAT5kit (Perkin Elmer TGRS5 S10K) and Alphascreen protein A kit (PerkinElmer 6760617M)

Methods:

Culture cells for about 16 h without EPO prior to running assay. Testcompounds or controls are dissolved and serially diluted in 100% DMSO.DMSO stocks are subsequently diluted 1:50 in cell culture media tocreate the 4× compound stocks (containing 2% DMSO). Using a Corningwhite 96 well, ½ area plate, cells are plated at 2×10⁵/10 μL/well in 10μL media followed by addition of 5 μL of 4× test compound stock induplicate. Cells are incubated with compound for about 0.5 h at about37° C. After incubation, 5 μL of EPO is added to afford a finalconcentration of 1 nM EPO. The contents of the wells are mixed bycarefully tapping sides of the plate several times followed byincubation at about 37° C. for about 20 min. 5 μL of 5× AlphaScreenlysis buffer are added followed by shaking on an orbital shaker forabout 10 min at room temperature. 30 μL/well of acceptor beads are addedafter reconstitution following Perkin Elmer's AlphaScreen protocol,covered with foil and shaken on orbital shaker for about 2 min on high,then about 2 h on low. Donor beads are reconstituted following PerkinElmer's AlphaScreen protocol instructions followed by addition of 12μL/well, covered with foil and shaken on an orbital shaker for about 2min on high, about 2 h on low. Plates are read on an EnVision readerfollowing Perkin Elmer's AlphaScreen protocol instructions.

Antigen-Induced Degranulation of RBL-2H3 Cells:

RBL-2H3 cells are maintained in T75 flasks at about 37° C. and 5% CO₂,and passaged every 3-4 days. To harvest cells, 20 mL of PBS is used torinse the flask once, and then 3 mL of Trypsin-EDTA is added andincubated at about 37° C. for about 2 min. Cells are transferred to atube with 20 mL medium, spun down at 1000 RPM at room temperature forabout 5 min and resuspended at 1×10⁶ cells/mL. Cells are sensitized byadding DNP-specific mouse IgE to a final concentration of 0.1 μg/mL. 50μL of cells are added to each well of a 96 well flat bottom plate(50×10³ cells/well) and incubated overnight at about 37° C. in 5% CO₂.The next day, compounds are prepared in 100% DMSO at 10 mM. Eachcompound is then serially diluted 1:4 six times in 100% DMSO. Eachcompound dilution is then diluted 1:20 and then 1:25, both dilutions inTyrode's buffer. Media is aspirated from the cell plates and the cellsare rinsed twice with 100 μL of Tyrode's buffer (prewarmed to about 37°C.). 50 μL of compounds diluted in Tyrode's buffer are added to eachwell and the plates are incubated for about 15 min at about 37° C. in 5%CO_(2.)50 μL of 0.2 μg/mL DNP-HSA in Tyrode's buffer is then added toeach well and the plates are incubated for about 30 min at about 37° C.in 5% CO₂. The final concentration of the various components in theincubation mix are 0.002-10 μM compounds, 0.1% DMSO, and 0.1 μg/mLDNP-HSA. As one control, 0.2% DMSO (no compound) in Tyrode's buffer isadded to a set of wells to determine maximum stimulated release. As asecond control, Tyrode's buffer without DNP-HSA is added to a set ofwells with containing 0.2% DMSO without compounds to determineunstimulated release. Each condition (compounds and controls) is set upin triplicate wells. At the end of the 30 min incubation, 50 μL ofsupernate is transferred to a new 96 well plate. The remaining supernatein the cell plates is aspirated and replaced with 50 μL of 0.1% TritonX-100 in Tyrode's buffer to lyse the cells. 50 μL of freshly prepared1.8 mM 4-Nitrophenyl N-acetyl-D-D-glucosaminide (pNAG) is then added toeach well of supernate and cell lysate and the plates are incubated forabout 60 min at about 37° C. in 5% CO₂. 100 μL of 7.5 mg/mL sodiumbicarbonate is added to each well to stop the reaction. The plates arethen read at 405 nm on a Molecular Devices SpectraMax 250 plate reader.

Calculation of Results

-   1) The plate background OD₄₀₅ obtained from wells containing    Tyrode's buffer and pNAG (no supernate or lysate) is subtracted from    the OD₄₀₅ reading for each well containing supernate or lysate.-   2) The release for each well is expressed as the percentage of the    total release for that well, where the total release is twice the    release in the supernate plus the release in the cell lysate. This    calculation corrects for variable cell number in each well.-   3) The maximum response is the mean response of wells containing    DNP-HSA but no compound.-   4) The minimum response is the mean response of wells containing no    DNP-HSA and no compound.-   5) The response in each compound well is calculated as a percentage    of the maximum response (expressed as % control) where the maximum    response is 100% and the minimum response is 0%.-   6) A dose response curve is generated for each compound and the IC₅₀    of the curve is calculated using Prism GraphPad software and    nonlinear least squares regression analysis.

Acute in vivo measurement of JAK inhibition by compounds is measuredusing the:

Concanavalin A (Con A)-Induced Cytokine Production in Lewis Rats

The test compound is formulated in an inert vehicle (for example but notlimited to 0.5% hydroxypropylmethyl cellulose (Sigma, cat #H3785)/0.02%Tween 80 (Sigma, cat #4780) in water) at the desired concentration toachieve doses in the range of 0.01-100 mg/kg. Six-week-old male Lewisrats (125 g-150 g) (Charles River Laboratories) are dosed with thecompound orally, at time zero (0 min). After about 30 min the rats areinjected intravenously (i.v.) with 10 mg/kg Concanavalin A (Con A,AmershamBioscience, cat #17-0450-01) dissolved in PBS (Invitrogen, cat#14190). About 4 h later, the rats are cardiac bled and their plasma isanalyzed for levels of IL-2 (ELISA kit: R&D Systems cat #R2000) andIFN-γ (ELISA kit: R&D Systems cat #RIF00).

Acute in vivo measurement of Fcγ receptor signaling inhibition of thecompounds is measured using the:

Reverse Passive Arthus Model

On day 0 OVA was made up at a concentration of 17.5 mg/mL, in PBS byrocking gently until a solution was formed. 2% Evans Blue solution(Sigma Aldrich, cat# E2129) was then added to double the volume for afinal concentration of 8.75 mg/mL of OVA and 1% Evans Blue dye. Anti-OVAantibody (Abazyme), stock concentration 10 mg/mL, was thawed and a 400μg/100 μL solution was made with PBS. Compounds were made up by addingthe vehicle, 0.5% HPMC with 0.02% Tween80, and vortexing for about 15seconds followed by homogenizing for a minimum of about 2 min at 28,000rpm until there was a fine particulate suspension with no clumps ofcompound. Rats were weighed and dosed with compound at a pre-determinedt-max based on pharmacokinetic studies. Animals were then placed undergeneral anesthesia with a 5% isoflourane and oxygen mixture and shaved.Using a ½ mL insulin syringe two sites were injected i.d., 1 site with100 μL of 400 μg/100 μL of anti-OVA antibody, and 1 site with 100 μL ofsterile PBS. Each site was then circled with permanent marker forexplant later. Right after i.d. injections animals were injected with200 μL of the OVA (10 mg/kg)/Evans Blue mixture i.v., using a ½ mLinsulin syringe. About four hours post injection animals wereeuthanized, bled via cardiac puncture and blood was collected using aplasma separating tube. Blood samples were stored on ice untilcentrifugation (within about 2 h of collection). Each injection site wasremoved with a disposable biopsy punch (Acuderm Acu-Punch Disposable 12mm), cut into four pieces and placed in a pre-labeled 2 mL eppendorftube. One mL of DMF was added to each biopsy tube and placed in a heatblock for about 24 h at about 50° C. About 24 h after incubation 100 μLof each sample was added to a 96 well flat bottom plate. The sampleswere read at 620 nm on a plate reader using the Softmax software.Background was removed by subtracting the OD from the PBS injected sitefrom the OD of the anti-OVA injected site for each individual animal.

Plasma samples were spun down in a microcentrifuge for about 5 min at16.1 ref. 200 μL of plasma was placed in a 1.7 mL eppendorf tube fordrug level measurement and tubes were stored at −80° C. untilevaluation.

Chronic in vivo effects of the compounds on anc arthritis disease modelis measured using the:

Adjuvant Induced Arthritis (AIA) in a Lewis Rat

Female Lewis rats, (6 weeks of age, 125 g-150 g in weight from CharlesRiver Laboratories) are immunized intradermally (i.d.) in the righthind-footpad with 100 μL of a suspension of mineral oil (Sigma, cat#M5905) and containing 200 μg M. tuberculosis, H37RA (Difco, cat#231141). The inflammation appears in the contra-lateral (left) hind pawseven days after the initial immunization. Seven days post immunization,the compound is formulated in an inert vehicle (for example but notlimited to 0.5% hydroxypropylmethyl cellulose (Sigma, cat #H3785)/0.02%Tween 80 (Sigma, cat #4780) in water) and dosed orally once or twice aday for at least 10 days. Baseline paw volume is taken on day 0 using awater displacement pleythsmograph (Vgo Basile North America Inc. PA19473, Model #7140). Rats are lightly anesthetized with an inhalantanesthetic (isoflurane) and the contra-lateral (left) hind paw is dippedinto the plethysmograph and the paw volume is recorded. The rats arescored every other day up to day 17 after immunization. On day 17 afterimmunization, all rats are exsanguinated by cardiac puncture underisoflurane anesthesia, and the left hind paw is collected to assess theimpact on bone erosion using micro-CT scans (SCANCO Medical,Southeastern, PA, Model #μCT 40) at a voxel size of 18 μm, a thresholdof 400, sigma-gauss 0.8, support-gauss 1.0. Bone volume and density isdetermined for a 360 μm (200 slice) vertical section encompassing thetarsal section of the paw. The 360 μm section is analyzed from the baseof the metatarsals to the top of the tibia, with the lower referencepoint fixed at the tibiotalarjunction. Drug exposure is determined inthe plasma using LC/MS. or the:

Collagen Induced Arthritis (CIA) in a Lewis Rat

On day-1 Collagen Type II (CII), soluble from bovine nasal septum(Elastin Products, cat#CN276) was weighed out for a dose of 600 μg/rat,0.01M acetic acid (150 μL HOAc USP grade. J. T. Baker, order#9522-03,and 250 mL Milli Q Water) was added for a concentration of 4 mg/mL. Thevial was covered with aluminum foil and placed on a rocker at about 4°C. overnight. On day 0 collagen stock solution was diluted 1:1 withIncomplete Freunds adjuvant (IFA) (Difco labs, cat#263910) using a glassHamilton luer lock syringe (SGE Syringe Perfection VWR cat#007230),final concentration 2 mg/mL. Female Lewis rats (Charles RiverLaboratories) acclimated for 7 days at the time of immunization weighingapproximately 150 g were anesthetized in an anesthesia chamber usingisoflurane (5%) and oxygen. Once the rats were completely anesthetized,they were transferred to a nose cone to maintain anesthesia during theinjections. Rats were shaved at the base of the tail, 300 μL of collagenwas injected i.d. on the rump of the rat, n=9 per group. 100 μL at threesites with a 500 μL leur lock syringe and a 27 g needle. IFA controlrats are injected in the same manner (n=6). The IFA is a 1:1 emulsionwith the 0.01M acetic acid. Boost was done on day 6 of the study.Shaving was not done on this day and injections were done in the samemanner as the immunization. The inflammation appears in both hind paws10 days after the initial immunization. 10 days post immunization, thecompound was formulated in an inert vehicle (for example but not limitedto 0.5% hydroxypropylmethyl cellulose (Sigma, cat #H3785)/0.02% Tween 80(Sigma, cat #4780) in water) and dosed orally once or twice a day for atleast 9 days. Baseline paw volume was taken on day 7 using a waterdisplacement pleythsmograph (Vgo Basile North America Inc. PA 19473,Model #7140). Rats were lightly anesthetized with an inhalant anesthetic(isoflurane) and both hind paws were dipped into the plethysmograph andthe paw volume was recorded. The rats were scored 2 to 3 times a week upto day 18 after immunization. On day 18 after immunization, all ratswere exsanguinated by cardiac puncture under isoflurane anesthesia, andthe hind paws were collected to assess the impact on bone erosion usingmicro-CT scans (SCANCO Medical, Southeastern, PA, Model #μCT 40) at avoxel size of 18 μm, a threshold of 400, sigma-gauss 0.8, support-gauss1.0. Bone volume and density was determined for a 360 μm (200 slice)vertical section encompassing the tarsal section of the paw. The 360 μmsection was analyzed from the base of the metatarsals to the top of thetibia, with the lower reference point fixed at the tibiotalar junction.Drug exposure was determined from plasma using LC/MS.

The teachings of all references, including journal articles, patents andpublished patent applications, are incorporated herein by reference intheir entirety.

The following examples are for illustrative purposes and are not to beconstrued as limiting the scope of the present invention.

General Synthetic Schemes

Compounds of the invention may be prepared using the synthetictransformations illustrated in Schemes I-XII. Starting materials arecommercially available, may be prepared by the procedures describedherein, by literature procedures, or by procedures that would be wellknown to one skilled in the art of organic chemistry. Methods forpreparing pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine compounds of theinvention are illustrated in Scheme I. In Scheme 1, step a, commerciallyavailable 2-bromo-5H-pyrrolo[2,3-b]pyrazine (also called5-bromo-4,7-diazaindole from Ark Pharm, Inc) is protected as asulfonamide using conditions such as those described in Preparation #1or by methods known to one skilled in the art (for example, Larock, R.C. “Comprehensive Organic Transformations: A Guide to Functional GroupPreparations, 2^(nd) edition”, 1999, Wiley-VCH or Greene, T. W. andWuts, P. G. M. “Protective Groups in Organic Synthesis, 3^(rd) Edition”,1999, Wiley-Interscience). Alternatively, protectedpyrrolo[2,3-b]pyrazine 2 can be prepared from commercially available3,5-dibromopyrazin-2-amine via a Sonogashira cross coupling (Scheme 1,step g) to give alkyne 9 which can be cyclized (Scheme 1, step h) toprovide pyrrolopyrazines 2 using methods known to one skilled in the art(for example Preparation #7, Method B). In Scheme I, step b, asubstituted hydrazine is introduced by reaction with pyrrolopyrazines 2under Buchwald-Hartwig amination conditions (for example, Preparation #2or Advanced Synthesis & Catalysis 2004, 346, 1599-1626) to givepyrrolopyrazines 3. If R″ is such that pyrrolopyrazines 3 contain ahydrazide (R″=—C(O)R′″) or hydrazone, the material may be directlycyclized to pyrrolotriazolopyrazines 6 using conditions such as thosedescribed in General Procedure C, the initial step of Example #1,General Procedure G or by methods known to one skilled in the art (forexample, Bioorganic & Medicinal Chemistry Letters 2007, 17(12),3373-3377 or Journal of Medicinal Chemistry 1990, 33(9), 2326-34). Insome cases, pyrrolotriazolopyrazines 6 may be reacted in situ to givepyrrolotriazolopyrazines 7 (for example, Example #1 or GeneralProcedures B and E). Additional reactions may also occur withoutisolation of initial pyrrolotriazolopyrazines 6 or 7 as seen in GeneralProcedures D and F. If R″ is a protecting group, deprotection ofcompounds 3 to yield hydrazinylpyrrolopyrazines 4 can be performed usingconditions such as those described in General Procedure I, GeneralProcedure J, or Greene, T. W. and Wuts, P. G. M. “Protective Groups inOrganic Synthesis, 3^(rd) Edition”, 1999, Wiley-Interscience. Forexample, a protecting group such as a t-butoxycarbonyl group can beremoved with acid using conditions such as those described inPreparation #3, General Procedure I or by methods known to one skilledin the art (for example, the books from Larock, R. C. or Greene, T. W.and Wuts, P. G. M. referenced above). Alternatively, reaction ofpyrrolopyrazines 2 with hydrazine under Buchwald-Hartwig aminationconditions as described above may give hydrazinylpyrrolopyrazines 4directly. The formation of hydrazides 5 from hydrazinylpyrrolopyrazines4 (Scheme I, step d) may be accomplished by a variety of methods knownto one skilled in the art including in situ conditions such as thosedescribed in Example #1, General Procedure A, or standard peptidecoupling methods such as those found in Larock, R. C. referenced above.The hydrazides 5 may be cyclized to pyrrolotriazolopyrazines 6 usingconditions such as those described in Example #1, General Procedure C,or by methods known to one skilled in the art (for example, Bioorganic &Medicinal Chemistry Letters 2007, 17(12), 3373-3377 or Journal ofMedicinal Chemistry 1990, 33(9), 2326-34). Further functionalization ofpyrrolotriazolopyrazines 6 can be performed, if desired, using reactionsknown to one skilled in the art (for example, Larock, R. C. referencedabove). For example, formation of amides, ureas, sulfonamides, arylamines, or heteroaryl amines can be prepared frompyrrolotriazolopyrazines 6 containing a primary or secondary amine (forexample, Examples #3 and #4 or General Procedures L, M, N or O). Also,deprotection of pyrrolotriazolopyrazines 6 can be performed usingconditions such as those described in Greene, T. W. and Wuts, P. G. M.referenced above or in General Procedures I or J. For example, aprotecting group such as a benzyloxycarbonyl group can be removed from aprotected amine to yield the unprotected amine (for example, Example #2)and the deprotected compounds 6 may then be reacted further as describedabove. Removal of the sulfonamide protecting group ofpyrrolotriazolopyrazines 6 may be accomplished using conditions such asthose described in Example #1, General Procedure H, or by methods knownto one skilled in the art (for example, the books from Larock, R. C. orGreene, T. W. and Wuts, P. G. M. referenced above) to givepyrrolotriazolopyrazines 7 (Scheme I, step f). Further functionalizationof the R group in pyrrolotriazolopyrazines 7 can be performed, ifdesired, using reactions known to one skilled in the art (for example,Larock, R. C. referenced above). For example, formation of amides,ureas, sulfonamides, aryl amines, or heteroaryl amines can be preparedfrom pyrrolotriazolopyrazines 7 with an R containing a primary orsecondary amine (for example, Examples #3 and #4 or General ProceduresL, M, N or O). Also, deprotection of the R group inpyrrolotriazolopyrazines 7 to yield an unprotected compound can beperformed using conditions such as those described in Greene, T. W. andWuts, P. G. M. referenced above or in General Procedures I or J. Forexample, a protecting group such as a benzyloxycarbonyl group can beremoved from a protected amine to yield the unprotected amine (forexample, Example #2 or General Procedure J) and the deprotectedcompounds 7 may then be reacted further as described above.

The formation of hydrazones 10 from hydrazinylpyrrolopyrazines 4 (SchemeII, step a) may be accomplished by a variety of methods known to oneskilled in the art including in situ conditions such as those describedin General Procedure G. The hydrazones 10 may be cyclized topyrrolotriazolopyrazines 6 using conditions such as those described inGeneral Procedure G or by methods known to one skilled in the art.Further functionalization of pyrrolotriazolopyrazines 6 can beperformed, if desired, using reactions known to one skilled in the art(for example, Larock, R. C. referenced above). Further functionalizationof pyrrolotriazolopyrazines 6 including sulfonamide hydrolysis to givepyrrolotriazolopyrazines 7 (Scheme I, step f) are described above.

Methods for preparing imidazo[1,2-a]pyrrolo[2,3-e]pyrazines compounds ofthe invention are illustrated in Scheme III. In step a, a carbamate isintroduced by reacting pyrrolopyrazines 2 with tert-butyl carbamateunder Buchwald-Hartwig amination conditions (for example, Example #8,Step A; Preparation #2, or Advanced Synthesis & Catalysis 2004, 346,1599-1626) to give pyrrolopyrazin-2-ylcarbamates 11. Deprotection ofcompounds II to yield 2-aminopyrrolopyrazine sulfonamides 12 can beperformed using conditions such as those described in Example #8, StepB; General Procedure I, or Greene, T. W. and Wuts, P. G. M.

“Protective Groups in Organic Synthesis, 3^(rd) Edition”, 1999,Wiley-Interscience. The formation of imidazopyrrolopyrazines 13substituted in the 7-position can be achieved by reacting2-aminopyrrolopyrazine sulfonamides 12 with appropriately substituted2-halomethyl ketones by methods known to one skilled in the art (forexample, Journal of Medicinal Chemistry, 1987, 30(11), 2031-2046 orExample #8, Step C). Further functionalization ofimidazopyrrolopyrazines 13 can be performed, if desired, using reactionsknown to one skilled in the art (for example, Larock, R. C. referencedabove). For example, formation of amides, ureas, sulfonamides, arylamines or heteroaryl amines can be prepared from imidazopyrrolopyrazines13 containing a primary or secondary amine (for example, Examples #3 and#4 or General Procedures L, M, N or O). Also, deprotection ofimidazopyrrolopyrazines 13 can be performed using conditions such asthose described in Greene, T. W. and Wuts, P. G. M. referenced above orin General Procedures I or J and the deprotected compounds 13 may thenbe reacted further as described above. Removal of the sulfonamideprotecting group of imidazopyrrolopyrazines 13 may be accomplished usingconditions such as those described in Example #8, Step D; GeneralProcedure H, or by methods known to one skilled in the art (for example,the books from Larock, R. C. or Greene, T. W. and Wuts, P. G. M.referenced above) to give imidazopyrrolopyrazines 14. Alternatively,alkylation of pyrrolopyrazin-2-ylcarbamates 11 with appropriatelysubstituted 2-halomethyl ketones by methods known to one skilled in theart (for example, Example #9, Step A; Tetrahedron Letters, 2006, 47(34),6113-6115; or Journal of Medicinal Chemistry, 2005, 48(14), 4535-4546)yields pyrrolopyrazines 15. Cyclization of pyrrolopyrazines 15 intoimidazopyrrolopyrazines 16 can be accomplished by methods known to oneskilled in the art (for example, Example #9, Step B; European Journal ofMedicinal Chemistry, 2001, 36(3), 255-264; or Bioorganic and MedicinalChemistry Letters, 2007, 17(5), 1233-1237). Further functionalization ofthe R group in imidazopyrrolopyrazines 16 can be performed, if desired,using reactions known to one skilled in the art (for example, Larock, R.C. referenced above). For example, formation of amides, ureas,sulfonamides, aryl amines, or heteroaryl amines can be prepared fromimidazopyrrolopyrazines 16 with an R′″ group containing a primary orsecondary amine (for example, Examples #3 and #4 or General ProceduresL, M, N or O). Also, deprotection of the R group inimidazopyrrolopyrazines 16 to yield an unprotected compound 17 can beperformed using conditions such as those described in Greene, T. W. andWuts, P. G. M. referenced above or in General Procedures I or J and thedeprotected compounds 17 may then be reacted further as described above.Removal of the sulfonamide protecting group of imidazopyrrolopyrazines16 may be accomplished using conditions such as those described inExample #9, Step C; General Procedure H, or by methods known to oneskilled in the art (for example, the books from Larock, R. C. or Greene,T. W. and Wuts, P. G. M. referenced above) to giveimidazopyrrolopyrazines 17.

Methods for preparing imidazo[1,5-a]pyrrolo[2,3-e]pyrazines compounds ofthe invention are illustrated in Scheme IV. In step a, a vinyl group isintroduced by reacting pyrrolopyrazines 2 with a boronic acid underSuzuki cross coupling conditions (for example, Example #10, Step A).Oxidative cleavage of the alkenes, 18, provides aldehydes 19 (forexample, Example #10, Step B). Conversion to the corresponding primaryamines can be accomplished by first condensation with hydroxylaminefollowed by reduction with zinc, providing amines 21 (for example,Example #10, Step C). Alternatively amines 21 can be prepared byreduction of aldehydes 19 to the corresponding alcohols (for example,Example #13, Step D), conversion of the alcohol to the chloride anddisplacement with azide to provide the azides 20 (for example, Example#13, Step E). Reduction of the azides provide amines 21 (for example,Example #13, Step F). Alternatively amines 21 can be prepared byconversion of bromides 2 to the corresponding nitrites 25 (for example,Preparation #28), followed by reduction to amines 21 (for example,Preparation #28). Coupling of amines 21 with acids provides amides 22(for example, Example #10, Step C). Cyclization of amides 22 can beaccomplished by conversion to the thioamide followed by treatment withan activating agent (such as a mercury salt, a silver salt or a coppersalt) providing the imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 23 (forexample, Example #10, Step D). Deprotection of compounds 23 to yieldimidazo[1,5-a]pyrrolo[2,3-e]pyrazines 24 can be performed usingconditions such as those described in Greene, T. W. and Wuts, P. G. M.“Protective Groups in Organic Synthesis, 3^(rd) Edition”, 1999,Wiley-Interscience, General Procedure H, or Example #10, Step E. Furtherfunctionalization of the R′″ group inimidazo[1,5-a]pyrrolo[2,3-e]pyrazines 23 orimidazo[1,5-a]pyrrolo[2,3-e]pyrazines 24 can be performed, if desired,using reactions known to one skilled in the art (for example, Larock, R.C. referenced above). For example, formation of amides, ureas,sulfonamides, aryl amines, or heteroaryl amines can be prepared fromcompounds 23 or 24 with an R′″ group containing a primary or secondaryamine (for example, General Procedures L, M, N or O). Also, deprotectionof the R′″ group in compounds 23 or 24 to yield an unprotected compoundcan be performed using conditions such as those described in Greene, T.W. and Wuts, P. G. M. referenced above or in General Procedures I or Jand the deprotected compounds may then be reacted further as describedabove.

Methods for preparing 3H-dipyrrolo[1,2-a:2′,3′-e]pyrazines compounds ofthe invention are illustrated in Scheme V. In step a, aldehyde 19 isreacted under Horner-Emmons conditions to provide α,β-unsaturatedketones 26 (for example, Example #11, Step A). Reduction of the doublebond provides the saturated ketones 27 (for example, Example #11, StepB). Cyclization to the tricycles 28 can be accomplished by treatment of27 with an activating agent by methods known to one skilled in the art(for example, Example #11, Step C). Deprotection of compounds 28 toyield 3H-dipyrrolo[1,2-a:2′,3′-e]pyrazines 29 can be performed usingconditions such as those described in Greene, T. W. and Wuts, P. G. M.“Protective Groups in Organic Synthesis, 3rd Edition”, 1999,Wiley-Interscience; General Procedure H, or Example #11, Step D. Furtherfunctionalization of the R′″ group in3H-dipyrrolo[1,2-a:2′,3′-e]pyrazines 28 or 29 can be performed, ifdesired, using reactions known to one skilled in the art (for example,Larock, R. C. referenced above). For example, formation of amides,ureas, sulfonamides, aryl amines, or heteroaryl amines can be preparedfrom compounds 28 or 29 with an R′″ group containing a primary orsecondary amine (for example, General Procedures L, M, N or O). Also,deprotection of the R′″ group in compounds 28 or 29 to yield anunprotected compound can be performed using conditions such as thosedescribed in Greene, T. W. and Wuts, P. G. M. referenced above or inGeneral Procedures I or J and the deprotected compounds may then bereacted further as described above.

Methods for preparing substituted cyclopentyl carboxylic acids 38 foruse in the preparation of compounds of the invention are illustrated inScheme VI. In step a, β-ketoesters 31 may be condensed with methyl4-chloroacetoacetate 30 to give cyclic β-ketoester enolate salts 32 (forexample, General Procedure BB). Decarboxylation of compounds 32 to giveα,β-unsaturated ketones 33 is accomplished by standard methods known toone skilled in the art (for example, General Procedure CC). As shown instep c, hydrogenation of α,β-unsaturated ketones 33 provides thesaturated ketones 34 (for example, General Procedure DD). Reductiveamination of ketones 34 with dibenzylamine yields compounds 35 usingconditions such as those described in General Procedure EE. Thedebenzylation of compounds 35 may be accomplished via hydrogenation asdescribed in General Procedure FF to give amines 36. Alternateconditions may be used to access amines 36 from ketones 34, for example,as described in Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations, 2^(nd) edition”, 1999,Wiley-VCH. Amines 36 may undergo further functionalization usingreactions known to one skilled in the art (for example, Larock, R. C.referenced above). For example, formation of amides, ureas,sulfonamides, aryl amines, or heteroaryl amines can be prepared fromamines 36 (for example, General Procedures L, M, N or O) to givecompounds 37. The ester of compounds 37 may be hydrolyzed under aqueousbase or acid conditions to give the desired carboxylic acids 38 (forexample, General Procedure GG or Larock, R. C. referenced above). Ifdesired, chiral separation of compounds 33, 34, 35, 36, 37, or 38 may bedone using methods known to one skilled in the art such as chiralpreparative HPLC (for example, General Procedure II).

Methods for preparing 4-substituted piperidine-3-carboxylic acidcompounds of the invention are illustrated in Scheme VII. In step a,4-substituted or unsubstituted nicotinic acids 39 may be fully saturatedusing methods that are known to one skilled in the art (for example,Example #13, Step G). The resulting piperidine carboxylic acid 40 may beprotected with a suitable amine protecting group such as those describedin Greene, T. W. and Wuts, P. G. M. “Protective Groups in OrganicSynthesis, 3rd Edition”, 1999, Wiley-Interscience; Larock, R. C.“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations, 2^(nd) edition”, 1999, Wiley-VCH; or Example #13, Step Gto give piperidine carboxylic acids 41.

Methods for preparing dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridinecompounds of the invention are illustrated in Scheme VIII. In step a,reaction of aldehyde 42 with a Grignard reagent provides alcohols 43using methods known to one skilled in the art (for example, Example #23,Step A). Preparation of ketones 44 (step b) can be accomplished bytreatment of alcohols 43 with an oxidizing agent by methods known to oneskilled in the art (for example, Example #23, Step B). Alternatively,ketones 44 can be prepared by reaction of heteroaryl iodide 45 with analdehyde (step c) to provide alcohols 43 (for example, Example #24, StepA) followed by oxidation as described previously. Preparation of ketones44 can be accomplished directly by reaction of heteroaryl iodide 45 withan appropriately substituted acid chloride by methods known to oneskilled in the art (such as Heterocycles, 2003, 59(1), 369-385). Ketones44 can then be converted to hydrazones 46 through reaction withhydrazine using conditions such as those described in Example #24, StepC. Cyclization of hydrazones 46 to providedihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridines 47 can be accomplished viaan intramolecular Buchwald-Hartwig cyclization (for example, Example#24, Step B, or Organic Letters, 2008, 10(18), 4109-4112). Furtherfunctionalization of the R′″ group indihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridines 47 can be performed, ifdesired, using reactions known to one skilled in the art (for example,Larock, R. C. referenced above). For example, formation of amides,ureas, sulfonamides, aryl amines, or heteroaryl amines can be preparedfrom compounds 47 with an R′″ group containing a primary or secondaryamine (for example, General Procedures L, M, N or O). Also, deprotectionof the R′″ group in compounds 47 to yield an unprotected compound can beperformed using conditions such as those described in Greene, T. W. andWuts, P. G. M. referenced above or in General Procedures I or J and thedeprotected compounds may then be reacted further as described above.

Methods for preparing isoxazolo[4,5-d]pyrrolo[2,3-b]pyridine compoundsof the invention are described in Scheme IX. Ketones 44 can be reactedwith hydroxylamine hydrochloride (step a) to provide oximes 48 bymethods known to one skilled in the art (for example, Example #28, StepA). Cyclization of oximes 48 to provide the desiredisoxazolo[4,5-d]pyrrolo[2,3-b]pyridines 49 (step b) is accomplishedusing methods known to one skilled in the art (for example, Example #28,Step B or Tetrahedron, 2007, 63(12), 2695-2711). Furtherfunctionalization of the R group inisoxazolo[4,5-d]pyrrolo[2,3-b]pyridines 49 can be performed, if desired,using reactions known to one skilled in the art (for example, Larock, R.C. referenced above). For example, formation of amides, ureas,sulfonamides, aryl amines, or heteroaryl amines can be prepared fromcompounds 49 with an R′″ group containing a primary or secondary amine(for example, General Procedures L, M, N or O). Also, deprotection ofthe R′″ group in compounds 49 to yield an unprotected compound can beperformed using conditions such as those described in Greene, T. W. andWuts, P. G. M. referenced above or in General Procedures I or J and thedeprotected compounds may then be reacted further as described above.

Methods for preparing 1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridinecompounds of the invention are described in Scheme X. Commerciallyavailable 4-chloro-1H-pyrrolo-[2,3-b]pyridine-5-carbaldehyde 50 isreacted with an appropriately substituted hydrazine or hydrazinehydrochloride (Scheme X, step a) to provide the desired1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridines 51 by methods known toone skilled in the art (for example, Example #27). Additionally, the1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridines 51 can be protected asa sulfonamide (Scheme X, step b) using conditions such as thosedescribed in Preparation #1 or by methods known to one skilled in theart (for example, Larock, R. C. “Comprehensive Organic Transformations:A Guide to Functional Group Preparations, 2^(nd) edition”, 1999,Wiley-VCH or Greene, T. W. and Wuts, P. G. M. “Protective Groups inOrganic Synthesis, 3^(rd) Edition”, 1999, Wiley-Interscience). Theprotected compounds 52 can be iodinated by methods known to one skilledin the art (for example, Example #42, Step C). Halogenated tricycles 53are reacted with an appropriately substituted boronic acid or esterunder Suzuki cross coupling conditions followed by deprotection to yielddihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridines 54 using conditions suchas those described in Example #42, Step D. Further functionalization ofthe R′″ group in dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridines 54 can beperformed, if desired, using reactions known to one skilled in the art(for example, Larock, R. C. referenced above). For example, formation ofamides, ureas, sulfonamides, aryl amines, or heteroaryl amines can beprepared from compounds 54 with an R′″ group containing a primary orsecondary amine (for example, General Procedures L, M, N or O). Also,deprotection of the R′″ group in compounds 54 to yield an unprotectedcompound can be performed using conditions such as those described inGreene, T. W. and Wuts, P. G. M. referenced above or in GeneralProcedures I or J and the deprotected compounds may then be reactedfurther as described above.

Methods for preparing 1,6-dihydrodipyrrolo[2,3-b:2′,3′-d]pyridinecompounds of the invention are described in Scheme XI. As shown in stepa, heteroaryl chlorides 55 are reacted with an appropriately substitutedamine using methods such as those described in Larock, R. C.“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations, 2^(nd) edition”, 1999, Wiley-VCH to give esters 56 withconcomitant deprotection. Esters 56 can be converted to thecorresponding aldehydes 57 (step b) and then cyclized to give thedesired 1,6-dihydrodipyrrolo[2,3-b:2′,3′-d]pyridines 58 using methodsknown to one skilled in the art (for example, Larock, R. C. referencedabove). Further functionalization of the R′″ group in1,6-dihydrodipyrrolo[2,3-b:2′,3′-d]pyridines 58 can be performed, ifdesired, using reactions known to one skilled in the art (for example,Larock, R. C. referenced above). For example, formation of amides,ureas, sulfonamides, aryl amines, or heteroaryl amines can be preparedfrom compounds 58 with an R′″ group containing a primary or secondaryamine (for example, General Procedures L, M, N or O). Also, deprotectionof the R group in compounds 58 to yield an unprotected compound can beperformed using conditions such as those described in Greene, T. W. andWuts, P. G. M. referenced above or in General Procedures I or J and thedeprotected compounds may then be reacted further as described above.

Methods for preparing imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 66 of theinvention are illustrated in Scheme XII.5-Bromo-3-((trimethylsilyl)ethynyl)pyrazine-2-amine 9 can be reactedwith an appropriately functionalized halide to give substituted alkynes59 (Scheme XII, step a) by methods known to one skilled in the art (forexample, Example #20, Step B). Alkynes 59 can be reacted under basicconditions to give pyrrolo[2,3-b]pyrazines 60 (as in Example #20, StepC). The pyrrolo[2,3-b]pyrazines 60 can be functionalized with anappropriate protecting group, such as (2-(trimethylsilyl)ethoxy)methyl,by methods known to one skilled in the art (for example, Greene, T. W.and Wuts, P. G. M. “Protective Groups in Organic Synthesis, 3^(rd)Edition”, 1999, Wiley-Interscience or Example #20, Step D).Pyrrolo[2,3-b]pyrazines 61 can be converted to the correspondinghydroxymethyl derivatives 62 through introduction of an alkene via aSuzuki cross coupling followed by oxidative cleavage and reduction ofthe intermediate aldehyde using methods known to one skilled in the art(for example, Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations, 2^(nd) edition”, 1999, Wiley-VCHor Example #20, Step E). Methanamines 63 can be prepared fromhydroxylmethyl compounds 62 (step e) by conversion to the azide (forexample, Example #20, Step F) followed by a Staudinger reduction usingmethods known to one skilled in the art (for example, Larock, R. C.referenced above or Example #20, Step G). The methanamines 63 can beconverted to an appropriately functionalized amides 64 using methodsknown to one skilled in the art (for example, Example #20, Step H).Amides 64 can be deprotected using methods known to one skilled in theart (for example, Greene, T. W. and Wuts referenced above or Example#20, Step I) to provide functionalized pyrrolo[2,3-b]pyrazines 65 (stepg). In Scheme XII, step h, cyclization of amides 65 can be accomplishedby conversion to the thioamide followed by treatment with an activatingagent providing the imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 66 (forexample, Example #20, Step J). Alternatively, cyclization of amides 64can be accomplished using the conditions described above (Scheme XII,step i) (for example, Example #22, Step B) followed by deprotection ofimidazo[1,5-a]pyrrolo[2,3-e]pyrazines 67 (Scheme XII, step j) usingmethods known to one skilled in the art (for example, Greene, T. W. andWuts referenced above or Example #22, Step C). Further functionalizationof the R′″ group in imidazo[1,5-a]pyrrolo[2,3-e]pyrazines 66 or 67 canbe performed, if desired, using reactions known to one skilled in theart (for example, Larock, R. C. referenced above). For example,formation of amides, ureas, sulfonamides, aryl amines, or heteroarylamines can be prepared from compounds 66 or 67 with an R′″ groupcontaining a primary or secondary amine (for example, General ProceduresL, M, N or O). Also, deprotection of the R′″ group in compounds 66 or 67to yield an unprotected compound can be performed using conditions suchas those described in Greene, T. W. and Wuts, P. G. M. referenced aboveor in General Procedures I or J and the deprotected compounds may thenbe reacted further as described above.

GENERAL PROCEDURES AND EXAMPLES

The general synthetic schemes that were utilized to construct themajority of compounds disclosed in this application are described belowin Schemes 1-39. These schemes are provided for illustrative purposesonly and are not to be construed as limiting the scope of the invention.

List of General Procedures

-   General Procedure A Formation of a hydrazide from a carboxylic acid-   General Procedure B Formation of a hydrazide from an acid chloride    followed by cyclization and sulfonamide hydrolysis-   General Procedure C Cyclization of a hydrazide-   General Procedure D Cyclization of a hydrazide followed by    sulfonamide hydrolysis and Boc-deprotection-   General Procedure E Cyclization of a hydrazide followed by    sulfonamide hydrolysis-   General Procedure F Cyclization of a hydrazide with loss of    Boc-protecting group followed by sulfonamide hydrolysis-   General Procedure G Formation of a hydrazone followed by cyclization    and sulfonamide hydrolysis-   General Procedure H Hydrolysis of a sulfonamide-   General Procedure I Acidic cleavage of a Boc-protected amine-   General Procedure J Deprotection of a Cbz-protected amine-   General Procedure K Formation of an amide from an activated acid and    an amine-   General Procedure L Formation of an amide from a carboxylic acid and    an amine-   General Procedure M Formation of a urea from an amine and a    carbamoyl chloride-   General Procedure N Formation of a sulfonamide from an amine-   General Procedure O Displacement of an aryl or heteroaryl halide    with an amine-   General Procedure P Boc-protection of an amine-   General Procedure Q Cbz-protection of an amine-   General Procedure R Reduction of a pyridine-   General Procedure S Reduction of an ester to an alcohol-   General Procedure T Oxidation of an alcohol to an aldehyde-   General Procedure U Formation of a semicarbazide-   General Procedure V Cyclization of a semicarbazide-   General Procedure W Formation of an acid chloride-   General Procedure X Formation of a urea using CDI-   General Procedure Y Formation of an ester from a carboxylic acid-   General Procedure Z N-Alkylation using an alkyl halide or    α-haloketone-   General Procedure AA Cyclization of an amide using a    dithiaphosphetane reagent-   General Procedure BB Knoevenagel condensation to form a substituted    cyclopentadiene-   General Procedure CC Decarboxylation of a β-ketoester enolate-   General Procedure DD Hydrogenation of an alkene-   General Procedure EE Reductive amination of a ketone or aldehyde-   General Procedure FF Debenzylation of an amine-   General Procedure GG Hydrolysis of an ester to a carboxylic acid-   General Procedure HH Dehydration of an amide to a nitrile-   General Procedure II Chiral preparative HPLC separation of    stereoisomers-   General Procedure JJ Acidic hydrolysis of an acetyl protected amine-   General Procedure KK Cyclopropanation using chloroiodomethane-   General Procedure LL Formation of a bromomethyl ketone from an acid    chloride-   General Procedure MM Reduction of an α,β-unsaturated ketone to an    allylic alcohol

The following examples are ordered according to the final generalprocedure used in their preparation. The synthetic routes to any novelintermediates are detailed by sequentially listing the general procedure(letter codes) in parentheses after their name with additional reactantsor reagents as appropriate. A worked example of this protocol is givenbelow using Example #H.1.1 as a non-limiting illustration. Example#H.1.1 isN-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)-3-chlorobenzenesulfonamide,which was prepared from3-chloro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)benzenesulfonamideusing General Procedure H as represented in Scheme A.

The precursor to Example #H.1.1,3-chloro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)benzenesulfonamide,was prepared as shown in Scheme B.2-Hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (Preparation #9) and4-(tert-butoxycarbonylamino)bicyclo-[2.2.2]octane-1-carboxylic acid arereacted following the conditions given in General Procedure A to givetert-butyl4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)bicyclo[2.2.2]octan-1-ylcarbamate.This hydrazide is cyclized using the conditions given in GeneralProcedure C to afford tert-butyl4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamate.This carbamate is deprotected using General Procedure I to yield4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine.This amine is sulfonylated using the conditions described in GeneralProcedure N to give the precursor to Example #H.1.1. The reactionsequence detailed above is translated in the preparations and examplessection to “using A from Preparation #9 and4-(tert-butoxycarbonylamino)bicyclo-[2.2.2]octane-1-carboxylic acid[Prime Organics], C with TEA, I, N from 3-chlorobenzenesulfonylchloride”.

Analytical Methods

Analytical data is included within the procedures below, in theillustrations of the general procedures, or in the tables of examples.Unless otherwise stated, all ¹H NMR data were collected on a VarianMercury Plus 400 MHz or a Varian Inova 600 MHz instrument and chemicalshifts are quoted in parts per million (ppm). LC/MS and HPLC data isreferenced to the table of LC/MS and HPLC conditions using the lowercase method letter provided in Table 2.

TABLE 2 LC/MS and HPLC methods Method Conditions a LC/MS: The gradientwas 5-60% B in 1.5 min then 60-95% B to 2.5 min with a hold at 95% B for1.2 min (1.3 mL/min flow rate). Mobile phase A was 10 mM NH₄OAc, mobilephase B was HPLC grade MeCN. The column used for the chromatography is a4.6 × 50 mm MAC-MOD Halo C8 column (2.7 μm particles). Detection methodsare diode array (DAD) and evaporative light scattering (ELSD) detectionas well as positive/negative electrospray ionization. b HPLC: Thegradient was 10-60% B over 40 min (25 mL/min flow rate). Mobile phase Awas 50 mM NH₄OAc (pH 4.5) and mobile phase B was HPLC grade MeCN. Thecolumn used for the chromatography was a 21.2 × 250 mm Hypersil C18 HScolumn (8 μm particles). Detection method is UV, λ = 254 nm. c HPLC: Thegradient was 10-100% B over 40 min, hold 5 min at 100% B, 2 min back to10% B, 4 min hold at 10% B (21 mL/min flow rate). Mobile phase A was 50mM NH₄OAc (pH 4.5) and mobile phase B was HPLC grade MeCN. The columnused for the chromatography was a 21.2 × 250 mm Hypersil C18 HS column(8 μm particles). Detection method is UV, λ = 344 nm. d LC/MS: Thegradient was 5-60% B in 0.75 min then 60-95% B to 1.15 min with a holdat 95% B for 0.75 min (1.3 mL/min flow rate). Mobile phase A was 10 mMNH₄OAc, mobile phase B was HPLC grade MeCN. The column used for thechromatography is a 4.6 × 50 mm MAC-MOD Halo C8 column (2.7 μmparticles). Detection methods are diode array (DAD) and evaporativelight scattering (ELSD) detection as well as positive/negativeelectrospray ionization. e HPLC: The gradient was 5-95% B over 20 min(21 mL/min flow rate). Mobile phase A was 50 mM NH₄OAc (pH 4.5) andmobile phase B was HPLC grade MeCN. The column used for thechromatography was a 21.2 × 250 mm Hypersil C18 HS column (8 μmparticles). Detection method is UV, λ = 254 nm. f HPLC: The gradient was0-30% B over 20 min (21 mL/min flow rate). Mobile phase A was 50 mMNH₄OAc (pH 4.5) and mobile phase B was HPLC grade MeCN. The column usedfor the chromatography was a 21.2 × 250 mm Hypersil C18 HS column (8 μmparticles). Detection method is UV, λ = 254 nm. g HPLC: The gradient was0-50% B over 20 min (21 mL/min flow rate). Mobile phase A was 50 mMNH₄OAc (pH 4.5) and mobile phase B was HPLC grade MeCN. The column usedfor the chromatography was a 21.2 × 250 mm Hypersil C18 HS column (8 μmparticles). Detection method is UV, λ = 254 nm. h HPLC: The gradient was20-60% B over 40 min (81 mL/min flow rate), mobile phase A was 50 mMNH₄OAc (pH 4.5) and mobile phase B was HPLC grade MeCN, the column usedfor the chromatography was a 25 × 250 mm Hypersil C18 HS column (10 μmparticles), detection method is UV, λ = 315 nm. i HPLC: The gradient was10-80% B over 9 min then 80-100% B over 0.10 min with a hold at 100% Bfor 1.50 min (22.5 mL/min flow rate). Mobile phase A was 50 mM NH₄OAc(pH 4.5) and mobile phase B was HPLC grade MeCN, the column used for thechromatography was a 19 × 50 mm Waters Atlantis T3 OBD C18 column (5 μmparticles), detection methods are Photodiode array DAD and Waters ZQ2000 mass spectrometer. j HPLC: The gradient was 0-40% B over 30 min (21mL/min flow rate). Mobile phase A was 50 mM NH₄OAc (pH 4.5) and mobilephase B was HPLC grade MeCN. The column used for the chromatography wasa 21.2 × 250 mm Hypersil C18 HS column (8 μm particles). Detectionmethod is UV, λ = 254 nm. k HPLC: The gradient was 25-100% B over 25 min(21 mL/min flow rate). Mobile phase A was 50 mM NH₄OAc (pH 4.5) andmobile phase B was HPLC grade MeCN. The column used for chromatographywas a 21.2 × 250 mm Hypersil HS C18 column (8 um particles). Detectionmethod is UV, λ = 380 nm. l LC/MS: The gradient was 0.1 min at 10% B,10-100% B over 2.5 min with a hold at 100% B for 0.3 min, then to 10% Bover 0.1 min. Mobile phase A was 0.1% TFA in water and mobile phase Bwas HPLC grade MeCN. The column used for the chromatography was a 2.1 mm× 30 mm Phenomenex Luna Combi-HTS C8(2) (5 μM particles). Detectionmethods are Waters 996 diode-array detector and Sedere Sedex-75 ELSD.The ZMD mass spectrometer was operated under positive APCI ionizationconditions. m HPLC: The gradient was 10-100% B over 50 min (21 mL/minflow rate). Mobile phase A was 50 mM NH₄OAc (pH 4.5) and mobile phase Bwas HPLC grade MeCN. The column used for the chromatography was a 21.2 ×250 mm Hypersil C18 HS column (8 μm particles). Detection method is UV,λ = 341 nm. n LC/MS: The gradient was 30-60% B in 1.50 min then 60-95% Bto 2.5 min with a hold at 95% B for 1.2 min (1.3 mL/min flow rate).Mobile phase A was 10 mM ammonium acetate, mobile phase B was HPLC gradeMeCN. The column used for the chromatography is a 4.6 × 50 mm MAC-MODHalo C8 column (2.7 μm particles). Detection methods are diode array(DAD) and evaporative light scattering (ELSD) detection as well aspositive/negative electrospray ionization. o LC/MS: The gradient was5-60% B in 1.5 min then 60-95% B to 2.5 min with a hold at 95% B for 1.2min (1.3 mL/min flow rate). Mobile phase A was 10 mM ammonium acetate,mobile phase B was HPLC grade MeCN. The column used for thechromatography is a 4.6 × 30 mm Vydac Genesis C8 column (4 μmparticles). Detection methods are diode array (DAD) as well aspositive/negative electrospray ionization and MS² data dependentscanning on the positive ion scan (45 eV collision energy). p HPLC: Thecolumn used for the chromatography was a 21.2 × 250 mm Hypersil C18 HScolumn (8 μm particles). The gradient was 5-95% B over 50 min (21 mL/minflow rate). Mobile phase A was 0.05 N aqueous ammonium acetate buffer(pH 4.5) and mobile phase B was HPLC grade MeCN. Detection method is UV,λ = 254 nm. q HPLC: The gradient was 10% to 50% B in 40 min (81 mL/minflow rate). Mobile phase A was 50 mM ammonium acetate in water, mobilephase B was HPLC grade MeCN. The column used for the chromatography wasa Microsorb C18, 100 Å, 5 μm, 46 × 250 mm column. Detection method isUV, λ = 310 nm. r HPLC: The gradient was 30% to 70% B in 40 min (81mL/min flow rate). Mobile phase A was 50 mM ammonium acetate in water,mobile phase B was HPLC grade MeCN. The column used for thechromatography was a Microsorb C18, 100 Å, 5 μm, 46 × 250 mm column.Detection method is UV, λ = 254 nm. s HPLC: The gradient was 10-40% Bover 50 min, 40-100% over 3 min, hold 5 min at 100% B, 2 min back to 10%B, 3 min hold at 10% B (21 mL/min flow rate). Mobile phase A was 50 mMNH₄OAc (pH 4.5) and mobile phase B was HPLC grade MeCN. The column usedfor the chromatography was a 21.2 × 250 mm Hypersil C18 HS column (8 μmparticles). Detection method is UV, λ = 326 nm. t HPLC: The column usedfor the chromatography is a 19 × 50 mm Waters Atlantis T-3 column (5 μmparticles). The gradient was 20-25% B in 3.0 min then 25-95% B to 9.00min with a hold at 95% B for 0.10 min (25 mL/min flow rate). Mobilephase A was 50 mM ammonium acetate, mobile phase B was HPLC gradeacetonitrile. Detection methods are Waters 2996 PDA and Mass Spec is aWaters ZQ 2000. Mass spec detection uses both pos/neg switching underAPCI ionization. u HPLC: The gradient was 5-100% B over 20 min (21mL/min flow rate). Mobile phase A was 50 mM NH₄OAc (pH 4.5) and mobilephase B was HPLC grade MeCN. The column used for the chromatography wasa 21.2 × 250 mm Hypersil C18 HS column (8 m particles). Detection methodis UV, λ = 254 nm.

TABLE 3 Chiral HPLC methods Method Conditions 1 The gradient was 5-60% Ain 19 min with a hold at 60% A for 2 min (20 mL/min flow rate). Mobilephase A was ethanol (200 proof), mobile phase B was HPLC grade heptanewith 0.1% diethylamine added. The column used for the chromatography wasa Daicel IC, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 2 The gradient was 30-58% A in 12 min (20 mL/min flow rate).Mobile phase A was HPLC grade isopropanol, mobile phase B is HPLC gradeheptane. The column used for the chromatography is a Daicel IA, 20 x 250mm column (5 μm particles). Detection methods were UV, λ = 280 nm,evaporative light scattering (ELSD) detection as well as opticalrotation. 3 Isocratic 30% A for 25 min (20 mL/min flow rate). Mobilephase A was ethanol (200 proof), mobile phase B was HPLC grade heptanewith 0.1% diethylamine added. The column used for the chromatography wasa Daicel IA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 4 Isocratic 20% A for 40 min (20 mL/min flow rate). Mobilephase A was ethanol (200 proof), mobile phase B was HPLC grade heptanewith 0.1% diethylamine added. The column used for the chromatography wasa Daicel IA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 5 The gradient was 30-65% A in 18 min (20 mL/min flow rate).Mobile phase A was HPLC grade isopropanol, mobile phase B was HPLC gradeheptane with 0.1% diethylamine added. The column used for thechromatography was a Daicel IA, 20 × 250 mm column (5 μm particles).Detection methods were UV, λ = 280 nm, evaporative light scattering(ELSD) detection as well as optical rotation. 6 The gradient was 10-55%A in 19 min with a hold at 55% for 0.5 min (20 mL/min flow rate). Mobilephase A was a 50:50 mixture of HPLC grade methanol and ethanol (200proof), mobile phase B was HPLC grade heptane with 0.1% diethylamineadded. The column used for the chromatography was a Daicel IA, 20 × 250mm column (5 μm particles). Detection methods were evaporative lightscattering (ELSD) detection as well as optical rotation. 7 The gradientwas 30-70% A in 18 min (20 mL/min flow rate). Mobile phase A was ethanol(200 proof), mobile phase B was HPLC grade heptane with 0.1%diethylamine added. The column used for the chromatography was a DaicelIC, 20 × 250 mm column (5 μm particles). Detection methods were UV, λ =280 nm, evaporative light scattering (ELSD) detection as well as opticalrotation. 8 Isocratic 20% A for 30 min (20 mL/min flow rate). Mobilephase A was HPLC grade isopropanol, mobile phase B was HPLC gradeheptane with 0.1% diethylamine added. The column used for thechromatography was a Daicel IA, 20 × 250 mm column (5 μm particles).Detection methods were evaporative light scattering (ELSD) detection aswell as optical rotation. 9 Isocratic 50% A for 25 min (20 mL/min flowrate). Mobile phase A was a 50:50 mixture of HPLC grade methanol andethanol (200 proof), mobile phase B was HPLC grade heptane with 0.1%diethylamine added. The column used for the chromatography was a DaicelIA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation. 10 Isocratic 70% A for 25 min (20 mL/min flow rate). Mobilephase A was ethanol (200 proof), mobile phase B was HPLC grade heptanewith 0.1% diethylamine added. The column used for the chromatography wasa Daicel IA, 20 × 250 mm column (5 μm particles). Detection methods wereevaporative light scattering (ELSD) detection as well as opticalrotation.

PREPARATIONS AND EXAMPLES

The general synthetic methods used in each General Procedure follow andinclude an illustration of a compound that was synthesized using thedesignated General Procedure. None of the specific conditions andreagents noted herein are to be construed as limiting the scope of theinvention and are provided for illustrative purposes only. All startingmaterials are commercially available from Sigma-Aldrich (including Flukaand Discovery CPR) unless otherwise noted after the chemical name.Reagent/reactant names given are as named on the commercial bottle or asgenerated by IUPAC conventions, CambridgeSoft® Chemdraw Ultra 9.0.7 orAutoNom 2000. Compounds designated as salts (e.g. hydrochloride,acetate) may contain more than one molar equivalent of the salt.

Preparation #1:2-Bromo-5-(4-tert-butylphenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine

A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (5.00 g, 25.2 mmol, ArkPharm) in DMF (150 mL) was cooled in an ice bath to about 0° C. and thenNaH (60% dispersion in mineral oil, 1.21 g, 30.3 mmol) was added. Afterabout 15 min, 4-tert-butylbenzene-1-sulfonyl chloride (6.46 g, 27.8mmol) was added. The reaction was maintained between about 0-10° C. forabout 2 h. Then, the reaction was diluted with water (200 mL) to give ayellow suspension. The solid was collected by vacuum filtration, whilewashing with additional water (100 mL), and dried in a vacuum oven atabout 70° C. to give2-bromo-5-(4-tert-butylphenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (9.05g, 91%): LC/MS (Table 2, Method a) R_(t)=3.05 min; MS m/z: 394/396(M+H)⁺.

Preparation #2: tert-Butyl2-(5-(4-tert-butylphenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylateand tert-butyl1-(5-(4-tert-butylphenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate

To a flask was added Pd₂(dba)₃ (5.06 g, 5.53 mmol),di-tert-butyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (4.70 g,11.06 mmol), and 1,4-dioxane (350 mL). The catalyst-ligand mixture wasdegassed via vacuum/nitrogen purge (3 times) and heated at about 80° C.for about 10 min. The reaction mixture is briefly removed from the oilbath then2-bromo-5-(4-tert-butylphenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (21.8g, 55.3 mmol, Preparation #1), tert-butyl hydrazinecarboxylate (36.5 g,276 mmol), and NaOt-Bu (7.97 g, 83 mmol) were added. After an additionalvacuum/nitrogen purge, the reaction was heated at about 80° C. for about5.5 h. The reaction was cooled to ambient temperature and filteredthrough Celite®, while washing with EtOAc (500 mL). The filtrate waswashed with saturated aqueous NH₄Cl (3×500 mL), saturated aqueous NaHCO₃(500 mL) and brine (500 mL), dried over anhydrous Na₂SO₄, filtered, andthen concentrated under reduced pressure to give about 55 g of a crudebrown oil. The brown oil was adsorbed onto silica and purified by silicagel chromatography eluting with a gradient of 10-50% EtOAc in heptane togive tert-butyl2-(5-(4-tert-butylphenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(4.51 g, 18% yield) and 4.68 g of a mixture of tert-butyl2-(5-(4-tert-butylphenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate[major regioisomer] and tert-butyl1-(5-(4-tert-butylphenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate[minor regioisomer]: LC/MS (Table 2, Method a) R_(t)=2.68 min; MS m/z:446 (M+H)⁺ [major regioisomer]; R_(t)=2.77 min; MS m/z: 446 (M+H)⁺[minor regioisomer].

Preparation #3:5-(4-tert-Butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine

To a mixture of tert-butyl2-(5-(4-tert-butylphenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylateand tert-butyl1-(5-(4-tert-butylphenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(11.24 g, 25.2 mmol, Preparation #2) in 1,4-dioxane (125 mL) was addedHCl (4 M in 1,4-dioxane, 125 mL, 500 mmol). The reaction mixture washeated at about 60° C. for about 1 h and then the reaction mixture wascooled to ambient temperature. The mixture was filtered, while washingwith Et₂O (150 mL), and the solid was partitioned between EtOAc (500 mL)and saturated aqueous NaHCO₃ (500 mL). The layers were separated and theorganic layer was washed with saturated aqueous NaHCO₃ and brine (200 mLeach), dried over anhydrous Na₂SO₄, filtered, concentrated under reducedpressure, and dried in a vacuum oven at about 70° C. to give5-(4-tert-butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine asa tan solid (7.54 g, 87%): LC/MS (Table 2, Method a) R_(t)=2.20 min; MSm/z: 346 (M+H)⁺.

Preparation #4: 2-Methylcyclohexanecarbonyl chloride

To a solution of 2-methylcyclohexanecarboxylic acid (6.00 mL, 42.6 mmol,mixture of cis and trans) in DCM (60 mL) was added oxalyl chloride (4.80mL, 55.3 mmol) followed by DMF (0.03 mL, 0.4 mmol). The reaction mixturewas stirred at ambient temperature for about 4 h before it wasconcentrated under reduced pressure to constant weight to afford2-methylcyclohexanecarbonyl chloride (mixture of diastereomers) as ayellow oil (7.0 g, 97%): ¹H NMR (400 MHz, CDCl₃) δ 2.98-2.94 (m, 1H),2.39-2.35 (m, 1H), 1.91-1.82 (m, 1H), 1.79-1.72 (m, 1H), 1.69-1.60 (m,2H), 1.57-1.47 (m, 2H), 1.42-1.36 (m, 1H), 1.34-1.26 (m, 1H), 1.04-0.96(m, 3H).

Preparation #5: Benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate

Step A: 1-(Benzyloxycarbonyl)piperidine-4-carboxylic acid

To a solution of piperidine-4-carboxylic acid (10.0 g, 77.4 mmol) andNa₂CO₃ (8.21 g, 77.4 mmol) in water (100 mL) was added a solution ofbenzyl 2,5-dioxopyrrolidin-1-yl carbonate (19.3 g, 77.4 mmol) in MeCN(100 mL). The reaction was stirred at ambient temperature for about 16 hand then concentrated under reduced pressure. The resulting aqueoussolution was quenched with NH₄Cl and was then extracted with EtOAc(2×100 mL). The combined organic extracts were dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to give1-(benzyloxycarbonyl)piperidine-4-carboxylic acid as a white solid (4.56g, 22%): LC/MS (Table 2, Method a) R_(t)=1.93 min; MS m/z: 262 (M−H)⁻.

Step B: Benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate

To a solution of 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (4.50g, 17.1 mmol, Preparation #5, Step A) in DCM (40 mL) at ambienttemperature was added oxalyl chloride (3.00 mL, 34.2 mmol) followed byDMF (0.10 mL, 1.3 mmol). After about 3 h, the reaction was concentratedunder reduced pressure to constant weight to afford benzyl4-(chlorocarbonyl)piperidine-1-carboxylate as a yellow oil (3.88 g,81%): ¹H NMR (CDCl₃) δ 7.44-7.35 (m, 5H), 5.16 (s, 2H), 4.20-4.10 (m,2H), 3.03-2.89 (m, 3H), 2.15-2.05 (m, 2H), 1.81-1.76 (m, 2H).

Preparation #6: Perfluorophenyl 2-cyanoacetate

To a solution of 2,3,4,5,6-pentafluorophenol (1.08 g, 5.88 mmol) and2-cyanoacetic acid (0.50 g, 5.9 mmol) in DCM (20 mL) was added DCC (1.21g, 5.88 mmol). After stirring for about 4 h at ambient temperature, thereaction was concentrated under reduced pressure and then purified oversilica gel (20 g) using DCM as the eluent to afford perfluorophenyl2-cyanoacetate as a white solid (1.39 g, 94%): ¹H NMR (400 MHz, CDCl₃) δ3.85 (s, 2H).

Preparation #7: 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

(Method A)

A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (78.0 g, 394 mmol, ArkPharm) in anhydrous DMF (272 mL) was added drop-wise over about 60 minto a stirred suspension of NaH (12.8 g, 532 mmol) in anhydrous DMF (543mL) at about 0-5° C. The brown reaction solution was stirred for about30 min at about 0-5° C. then a solution of p-toluenesulfonyl chloride(94.0 g, 492 mmol) in anhydrous DMF (272 mL) was added drop-wise overabout 60 min at about 0-5° C. The reaction mixture was stirred at about0-5° C. for about 1 h then allowed to warm to ambient temperature andstirred for about 18 h at ambient temperature. The reaction mixture waspoured slowly into ice water (6 L), followed by the addition of aqueous2.5 N NaOH (50.0 mL, 125 mmol). The precipitate was collected byfiltration and stirred with cold water (3×200 mL). The solid wascollected by filtration and dried to constant weight in a vacuum oven atabout 55° C. to yield 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (134.6g, 97%) as a pale beige solid: LC/MS (Table 2, Method d) R_(t)=1.58 min;MS m/z: 352/354 (M+H)⁺.

Preparation #7: 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

(Method B)

Step A: 5-Bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

To a solution of 3,5-dibromopyrazin-2-amine (40.0 g, 158 mmol), TEA(66.1 mL, 475 mmol), and copper(I) iodide (0.301 g, 1.58 mmol) in THF(1172 ml) was added PdCl₂(PPh₃)₂ (1.11 g, 1.58 mmol). The reactionmixture was cooled at about 0° C. and a solution of(trimethylsilyl)acetylene (20.8 mL, 150 mmol) in THF (146 mL) was addeddrop-wise. The reaction mixture was stirred at about 0-10° C. for about7 h and then concentrated under reduced pressure. The dark brown residuewas dissolved in DCM (600 mL) and filtered through a Celite® pad (3 cmin height×9 cm in diameter) while eluting with DCM (300 mL). Thefiltrate was washed with water (2×500 mL) and brine (500 mL), dried overanhydrous MgSO₄, filtered through a Florisil® pad (1 cm in height by 9cm in diameter) while washing with DCM/MeOH (9:1, 200 mL), andconcentrated under reduced pressure to give a brown solid. The solid wastriturated and sonicated with warm petroleum ether (b.p. 30-60° C., 250mL), cooled and collected, washing with petroleum ether (b.p. 30-60° C.;2×100 mL), and dried in a vacuum oven at about 70° C. to give5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (34.6 g, 70%): LC/MS(Table 2, Method d) R_(t)=1.59 min; MS m/z: 272 (M+H)⁺.

Step B: 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(3.00 g, 11.1 mmol) in DMF (60 mL) at about 0° C. was added NaH (60%dispersion in mineral oil, 0.577 g, 14.4 mmol) in three portions. Afterabout 15 min, p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) was addedand the reaction was allowed to warm slowly to ambient temperature.After about 16 h, the reaction mixture was poured onto ice-cold water(120 mL) and the precipitate was collected by vacuum filtration. Thecrude solid was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with DCM. The product-containing fractions wereconcentrated under reduced pressure to give2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.16 g, 52%): LC/MS (Table 2,Method d) R_(t)=1.58 min; MS m/z: 352/354 (M+H)⁺.

Preparation #8: tert-Butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate

To a flask was added Pd₂(dba)₃ (3.90 g, 4.26 mmol),di-tert-butyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (3.62 g,8.52 mmol), and anhydrous 1,4-dioxane (453 mL). The catalyst-ligandmixture was degassed via vacuum/nitrogen purge (3 times) and heated atabout 80° C. for about 10 min. The reaction mixture is briefly removedfrom the oil bath then 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0g, 85 mmol, Preparation #7), tert-butyl hydrazinecarboxylate (16.9 g,128 mmol), and NaOt-Bu (12.28 g, 128 mmol) were added. After anadditional vacuum/nitrogen purge, the reaction was heated at about 80°C. After about 50 min, the reaction mixture was cooled to ambienttemperature and filtered through a pad of silica gel (6 cm in height×6cm in diameter), topped with Celite® (1 cm in height×6 cm in diameter),while washing with EtOAc (3×150 mL). Water (300 mL) was added to thefiltrate and the organic layer was separated. The aqueous layer wasextracted with additional EtOAc (3×200 mL). The combined organicextracts were washed with saturated aqueous NH₄Cl, saturated aqueousNaHCO₃, and brine (400 mL each), dried over anhydrous MgSO₄, filtered,and concentrated under reduced pressure to give a dark brown oil (45 g).The brown oil was dissolved in DCM (250 mL), silica gel (200 g) wasadded, and the mixture was concentrated under reduced pressure. Theresulting silica mixture was purified using silica gel chromatographyeluting with a gradient of 25-65% EtOAc in heptane to give a mixture oftert-butyl 2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate[major regioisomer] and tert-butyl1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [minorregioisomer] (18.8 g, 50%): LC/MS (Table 2, Method d) R_(t)=1.47 min; MSm/z: 404 (M+H)⁺.

Preparation #9: 2-Hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(18.8 g, 46.6 mmol, Preparation #8) in 1,4-dioxane (239 mL) was addedHCl (4 M in 1,4-dioxane, 86 mL, 345 mmol). The reaction was heated atabout 60° C. for about 1 h and then cooled to about 15-20° C. The solidwas collected by vacuum filtration, washed with cold 1,4-dioxane (2×20mL), and then stirred with a solution of saturated NaHCO₃ and water(1:1, 150 mL). After about 1 h, the effervescence had subsided and thesolid was collected by vacuum filtration, washed with ice cold water(3×20 mL), and dried in a vacuum oven to a constant weight to afford2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a light yellowishbrown solid (8.01 g, 50%): LC/MS (Table 2, Method d) R_(t)=1.28 min; MSm/z: 304 (M+H)⁺.

Preparation #10: (R)-tert-Butyl1-(chlorocarbonyl)pyrrolidin-3-ylcarbamate

A flask was charged with (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.0 g,5.4 mmol, Lancaster) in DCM (15 mL) to give a colorless solution.Pyridine (0.89 mL, 10.8 mmol) was added and the solution was cooled toabout 0° C., followed by the addition of triphosgene (0.64 g, 2.1 mmol).The mixture was stirred for about 1 h while slowly warming to ambienttemperature. To the reaction solution was added DCM (50 mL) and thesolution was washed with water (20 mL) and HCl (1N, 10 mL). The organicportion was separated, dried over anhydrous MgSO₄, filtered, andconcentrated to dryness under reduced pressure to give (R)-tert-butyl1-(chlorocarbonyl)pyrrolidin-3-ylcarbamate (1.3 g, 98%) as a yellow oil:¹H NMR (DMSO-d₆) δ 7.28 (s, 1 H), 4.03 (m, 1 H), 3.73-3.20 (m, 4 H),2.05 (m, 1 H), 1.81 (m, 1 H), 1.39 (s, 9 H).

Preparation #11:(1R,2S,4R,5S)-4-(Cyclopropanesulfonamido)-1-methylbicyclo[3.1.0]hexane-2-carboxylicacid and(1S,2R,4S,5R)-4-(cyclopropanesulfonamido)-1-methylbicyclo[3.1.0]hexane-2-carboxylicacid

Step A: (1R,2S,4R,5S)-Ethyl4-hydroxy-1-methylbicyclo[3.1.0]hexane-2-carboxylate and(1S,2R,4S,5R)-ethyl 4-hydroxy-1-methylbicyclo[3.1.0]hexane-2-carboxylate

cis-Ethyl-4-hydroxy-2-methylcyclopent-2-enecarboxylate (0.96 g, 5.64mmol, Preparation #MM.1) and chloroiodomethane (4.97 g, 28.2 mmol) werereacted according to General Procedure KK to give (1R,2S,4R,5S)-ethyl4-hydroxy-1-methylbicyclo[3.1.0]hexane-2-carboxylate and(1S,2R,4S,5R)-ethyl 4-hydroxy-1-methylbicyclo[3.1.0]hexane-2-carboxylate(0.59 g, 57%) after purification by flash silica gel chromatographyeluting with a gradient of 30-60% EtOAc/heptane: ¹H NMR (400 MHz, CDCl₃)δ 4.60-4.51 (m, 1H), 4.23-4.10 (m, 2H), 2.74 (dd, J=8.0, 10.9 Hz, 1H),2.13 (m, 1H), 1.51 (m, 1H), 1.46-1.40 (m, 1H), 1.35-1.29 (m, 1H), 1.28(m, 6H), 1.09-1.04 (m, 1H), 0.37 (dd, J=5.7, 7.9 Hz, 1H).

Step B: (1R,2S,5S)-Ethyl1-methyl-4-oxobicyclo[3.1.0]hexane-2-carboxylate and (1S,2R,5R)-ethyl1-methyl-4-oxobicyclo[3.1.0]hexane-2-carboxylate

A mixture of (1R,2S,4R,5S)-ethyl4-hydroxy-1-methylbicyclo[3.1.0]hexane-2-carboxylate and(1S,2R,4S,5R)-ethyl 4-hydroxy-1-methylbicyclo[3.1.0]hexane-2-carboxylate(0.59 g, 3.2 mmol) was subjected to General Procedure T to give(1R,2S,5S)-ethyl 1-methyl-4-oxobicyclo[3.1.0]hexane-2-carboxylate and(1S,2R,5R)-ethyl 1-methyl-4-oxobicyclo[3.1.0]hexane-2-carboxylate (0.38g, 65%) after purification by silica gel chromatography eluting with agradient of 20-50% EtOAc/pentane: ¹H NMR (400 MHz, CDCl₃) δ 4.35-4.15(m, 2H), 3.12 (t, J=9.3 Hz, 1H), 2.60 (dd, J=9.2, 18.3 Hz, 1H),2.37-2.23 (m, 1H), 1.68 (dd, J=3.4, 9.2 Hz, 1H), 1.48 (s, 3H), 1.41 (dd,J=3.4, 5.2 Hz, 1H), 1.34 (t, J=7.1 Hz, 3H), 1.14 (dd, J=5.3, 9.2 Hz,1H).

Step C: (1R,2S,4R,5S)-Ethyl4-(cyclopropanesulfonamido)-1-methylbicyclo[3.1.0]hexane-2-carboxylateand (1S,2R,4S,5R)-ethyl4-(cyclopropanesulfonamido)-1-methylbicyclo[3.1.0]hexane-2-carboxylate

To a vial containing (1R,2S,5S)-ethyl1-methyl-4-oxobicyclo[3.1.0]hexane-2-carboxylate and (1S,2R,5R)-ethyl1-methyl-4-oxobicyclo[3.1.0]hexane-2-carboxylate (0.305 g, 1.67 mmol)was added a solution of ammonia (2 Nin EtOH) followed by titanium(IV)isopropoxide (0.54 mL, 1.8 mmol). The vial was capped and the reactionwas stirred at room temperature overnight. Sodium borohydride (0.095 g,2.5 mmol) was added and reaction mixture was stirred for about 5 h.Concentrated NH₄OH (5 mL) was added and the resulting mixture wasstirred for about 5 min. The resulting suspension was filtered and thefilter cake was washed with EtOAc (60 mL). The filtrate was partitionedand the aqueous layer was extracted with EtOAc (30 mL). The combinedorganic layer was washed with brine, dried over anhydrous MgSO₄,filtered, and concentrated to yield (1R,2S,4R,5S)-ethyl4-amino-1-methylbicyclo[3.1.0]hexane-2-carboxylate and(1S,2R,4S,5R)-ethyl 4-amino-1-methylbicyclo[3.1.0]hexane-2-carboxylate(0.21 g, 69%). This amine (0.212 g, 1.16 mmol) was reacted withcyclopropanesulfonyl chloride (0.244 g, 1.74 mmol) using GeneralProcedure N to give (1R,2S,4R,5S)-ethyl4-(cyclopropanesulfonamido)-1-methylbicyclo[3.1.0]hexane-2-carboxylateand (1S,2R,4S,5R)-ethyl4-(cyclopropanesulfonamido)-1-methylbicyclo[3.1.0]hexane-2-carboxylate(0.11 g, 33%): LC/MS (Table 2, Method a) R_(t)=2.06 min; MS m/z: 286(M−H)⁻.

Step D:(1R,2S,4R,5S)-4-(Cyclopropanesulfonamido)-1-methylbicyclo[3.1.0]hexane-2-carboxylicacid and(1S,2R,4S,5R)-4-(cyclopropanesulfonamido)-1-methylbicyclo[3.1.0]hexane-2-carboxylicacid.

A mixture of (1R,2S,4R,5S)-ethyl4-(cyclopropanesulfonamido)-1-methylbicyclo[3.1.0]hexane-2-carboxylateand (1S,2R,4S,5R)-ethyl4-(cyclopropanesulfonamido)-1-methylbicyclo[3.1.0]hexane-2-carboxylate(0.109 g, 0.379 mmol) was hydrolyzed using General Procedure GG to give(1R,2S,4R,5S)-4-(cyclopropanesulfonamido)-1-methylbicyclo[3.1.0]hexane-2-carboxylicacid and(1S,2R,4S,5R)-4-(cyclopropanesulfonamido)-1-methylbicyclo[3.1.0]hexane-2-carboxylicacid (0.113 g, 100%): LC/MS (Table 2, Method a) R_(t)=1.57 min; MS m/z:258 (M−H)⁻.

Preparation #12:(1R,2R,4S)-4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanecarboxylicacid and(1S,2S,4R)-4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanecarboxylicacid

Step A: (2R,4S)-Ethyl4-(dibenzylamino)-2-ethyl-1-methylcyclopentanecarboxylate and(2S,4R)-ethyl 4-(dibenzylamino)-2-ethyl-1-methylcyclopentanecarboxylate

To a solution of LDA (1.8M in THF, 3.04 mL, 5.47 mmol,) and THF (40 mL)at about −78° C. was added ethyl4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (1.0 g, 2.7 mmol,Preparation #EE.1) in THF (4 mL). The reaction mixture was stirred atabout −78° C. for about 1 h. MeI (2.57 mL, 41.0 mmol) was added andreaction mixture was stirred at about −78° C. for about 1 h and was thenwarmed to about −40° C. DCM (150 mL) was added followed by saturatedaqueous NH₄Cl solution (50 mL). The layers were separated and theaqueous layer was extracted with DCM (2×30 mL). The combined organiclayers were washed with brine, dried over anhydrous MgSO₄, filtered, andconcentrated to dryness under reduced pressure. The residue was purifiedby flash silica gel chromatography eluting with a gradient of 0-10%EtOAc in DCM to give (2R,4S)-ethyl4-(dibenzylamino)-2-ethyl-1-methylcyclopentanecarboxylate and(2S,4R)-ethyl 4-(dibenzylamino)-2-ethyl-1-methylcyclopentanecarboxylate(0.864 g, 84%). LC/MS (Table 2, Method a) R_(t)=2.25 min; MS m/z: 380(M+H)⁺.

Step B: (2R,4S)-Ethyl 4-amino-2-ethyl-1-methylcyclopentanecarboxylateand (2S,4R)-ethyl 4-amino-2-ethyl-1-methylcyclopentanecarboxylate

A mixture of (2R,4S)-ethyl4-(dibenzylamino)-2-ethyl-1-methylcyclopentanecarboxylate and(2S,4R)-ethyl 4-(dibenzylamino)-2-ethyl-1-methylcyclopentanecarboxylate(0.864 g, 2.28 mmol) was debenzylated using General Procedure FF to give(2R,4S)-ethyl 4-amino-2-ethyl-1-methylcyclopentanecarboxylate and(2S,4R)-ethyl 4-amino-2-ethyl-1-methylcyclopentanecarboxylate (0.45 g,100%). LC/MS (Table 2, Method a) R_(t)=1.55 min; MS m/z: 200 (M+H)⁺.

Step C: (1S,2R,4S) and (1R,2S,4R)-Ethyl4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanecarboxylate,(1R,2R,4S) and (1S,2S,4R)-ethyl4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanecarboxylate

A mixture of (2R,4S)-ethyl4-amino-2-ethyl-1-methylcyclopentanecarboxylate and (2S,4R)-ethyl4-amino-2-ethyl-1-methylcyclopentanecarboxylate (0.454 g, 2.28 mmol) wasprotected using General Procedure P. The crude reaction mixture waspurified by silica gel chromatography eluting with a gradient of 0-25%EtOAc/heptane to afford (1S,2R,4S) and (1R,2S,4R)-ethyl4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanecarboxylate(0.180 g, 26%): ¹H NMR (400 MHz, CDCl₃) δ 4.46 (s, 1H), 4.12 (q, J=7.1Hz, 2H), 4.07-3.93 (m, 1H), 2.65 (dd, J=9.2, 13.8 Hz, 1H), 2.36 (s, 1H),2.24-2.08 (m, 1H), 1.57 (m, 1H), 1.54-1.39 (m, 10H), 1.34-1.17 (m, 4H),1.17-1.05 (m, 4H), 0.87 (t, J=7.4 Hz, 3H), (1R,2R,4S) and(1S,2S,4R)-ethyl4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanecarboxylate(0.430 g, 63%): ¹H NMR (400 MHz, CDCl₃) δ 5.18 (s, 1H), 4.24-4.04 (m,3H), 2.46-2.33 (m, 1H), 1.97 (m, 2H), 1.63-1.50 (m, 2H), 1.48-1.34 (m,9H), 1.3-1.17 (m, 7H), 1.04-0.92 (m, 1H), 0.89 (t, J=7.1 Hz, 3H).

Step D: (1R,2R,4S) and(1S,2S,4R)-4-(tert-Butoxycarbonylamino)-2-ethyl-1-methylcyclopentanecarboxylicacid

A mixture of (1R,2R,4S) and (1S,2S,4R)-ethyl4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanecarboxylate(0.430 g, 1.44 mmol) was hydrolyzed according to General procedure GG togive (1R,2R,4S) and(1S,2S,4R)-4-(tert-Butoxycarbonylamino)-2-ethyl-1-methylcyclopentanecarboxylicacid (0.256 g, 86%): LC/MS (Table 2, Method a) R_(t)=2.22 min; MS m/z:270 (M−H)⁻.

Preparation #13: (1S,2R,4S) and(1R,2S,4R)-4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanecarboxylicacid

A mixture of (1S,2R,4S) and (1R,2S,4R)-ethyl4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanecarboxylate(0.180 g, 0.600 mmol) was hydrolyzed according to General procedure GGto give(1S,2R,4S)-4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanecarboxylicacid and(1S,2R,4S)-4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanecarboxylicacid (0.083 g, 51%): LC/MS (Table 2, Method a) R_(t)=2.23 min; MS m/z:270 (M−H)⁻.

Preparation #14:(1R,2S,4R,5R)-4-(tert-Butoxycarbonylamino)-6-(trimethylsilyl)bicyclo[3.1.0]hexane-2-carboxylicacid

Step A: (1R,4S)-tert-Butyl3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate

To a solution of (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (1.50 g,13.7 mmol) in THF (100 mL) was added TEA (1.90 mL, 13.7 mmol) and DMAP(0.27 g, 2.2 mmol). The mixture was stirred for about 5 min at about 0°C. followed by the addition of di-tert-butyl dicarbonate (3.40 mL, 14.4mmol) in THF (15 mL). The reaction was stirred at ambient temperaturefor about 24 h. The solvent was removed under reduced pressure and thecrude residue was taken up in DCM (50 mL) and washed with water (25 mL)and brine (25 mL). The organic layer was dried over anhydrous MgSO₄,filtered, and concentrated under reduced pressure. The crude materialwas purified by silica gel chromatography eluting with a gradient of0-30% EtOAc/heptane to afford (1R,4S)-tert-butyl3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (2.7 g, 93%) as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.26-6.86 (dd, 1H), 6.86-6.64(m, 1H), 5.08-4.78 (d, 1H), 3.52-3.21 (dd, 1H), 2.32-2.24 (d, 1H),2.09-2.02 (d, 1H), 1.05-1.36 (s, 9H).

Step B:(1S,2R,4R,5R)-7-Oxo-3-trimethylsilanyl-6-aza-tricyclo[3.2.1.0(2,4)]octane-6-carboxylicacid tert-butyl ester

To a solution of (1R,4S)-tert-butyl3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (1.3 g, 6.2 mmol) andpalladium(II) acetate (0.070 g, 0.31 mmol) in Et₂O (62 mL) was addedtrimethylsilyldiazomethane (2 M in hexanes, 3.00 mL, 11.5 mmol)drop-wise at ambient temperature over about 1 h. The mixture was stirredat ambient temperature for about 18 h and filtered through Celite®. TheCelite® pad was washed with Et₂O (50 mL) and the filtrate wasconcentrated under reduced pressure. The crude material was purified bysilica gel chromatography eluting with a gradient of 0-30% EtOAc/heptaneto afford(1S,2R,4R,5R)-7-oxo-3-trimethylsilanyl-6-aza-tricyclo[3.2.1.0(2,4)]octane-6-carboxylicacid tert-butyl ester (1.7 g, 92%). ¹H NMR (400 MHz, DMSO-d₆) δ 4.37 (s,1H), 2.70 (s, 1H), 1.45 (m, 10H), 1.23 (t, 1H), 0.76 (t, 1H), 0.10 (s,2H), −0.03 (s, 9H).

Step C:(1R,2S,4R,5R)-4-(tert-Butoxycarbonylamino)-6-(trimethylsilyl)bicyclo[3.1.0]hexane-2-carboxylicacid

A mixture of(1S,2R,4R,5R)-7-oxo-3-trimethylsilanyl-6-aza-tricyclo[3.2.1.0(2,4)]octane-6-carboxylicacid tert-butyl ester (1.7 g, 5.7 mmol) and potassium fluoride onalumina (2.10 g, 14.1 mmol) in THF (38 mL) was heated to about 60° C.for about 18 h. The mixture was cooled to ambient temperature andfiltered through Celite®. The Celite® pad was rinsed with EtOAc (50 mL)and the filtrate was concentrated under reduced pressure to afford(1R,2S,4R,5R)-4-(tert-butoxycarbonylamino)-6-(trimethylsilyl)bicyclo[3.1.0]hexane-2-carboxylicacid (1.82 g, 100%): LC/MS (Table 2, Method a) R_(t)=2.62 min; MS m/z:312 (M−H)⁻.

Preparation #15:(1R,2R,4S,5S)-4-(6-Tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[3.1.0]hexan-2-amine

To a solution of tert-butyl(1R,2R,4S,5R,)-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-6-(trimethylsilyl)bicyclo[3.1.0]hexan-2-ylcarbamate(0.780 g, 1.34 mmol, prepared using A from Preparation #9 andPreparation #14 with HATU, C with TEA) in DCM (20 mL) was addedtrifluoromethanesulfonic acid (0.48 mL, 5.4 mmol). After stirring atambient temperature for about 18 h, additional trifluoromethanesulfonicacid (0.48 mL, 5.4 mmol) was added and the mixture was stirred for aboutan additional 18 h. The reaction mixture was diluted with DCM (40 mL)and slowly poured into a vigorously stirred slurry of ice water (30 mL).After about 5 min the reaction mixture was neutralized with saturatedaqueous NaHCO₃. The layers were separated and the aqueous layer wasextracted with DCM (40 mL). The combined organic layers were washed withbrine, dried over anhydrous MgSO₄, filtered, and concentrated underreduced pressure to afford to afford(1R,2R,4S,5S)-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[3.1.0]hexan-2-amineas a light brown solid (0.55 g, 87%): LC MS (Table 2, Method a)R_(t)=1.75 min; MS m/z: 409 (M+H)⁺.

Preparation #16: Lithium(R)-4-(tert-butoxycarbonyl)-1-methylpiperazine-2-carboxylate

Step A: (R)-1-tert-Butyl 3-methyl 4-methylpiperazine-1,3-dicarboxylate

To (R)-1-tert-butyl 3-methylpiperazine-1,3-dicarboxylate (1.2 g, 4.9mmol, ASW Med Chem Inc) in MeCN and MeOH (1:1, 100 mL) was addedformaldehyde (37% aqueous, 13.2 mL, 177 mmol), followed by the additionof sodium triacetoxyborohydride (5.20 g, 24.5 mmol). The mixture wasstirred for about 15 min at ambient temperature. AcOH (5.6 mL, 98 mmol)was added drop-wise and the mixture was stirred for about 1 h. Thesolvent was removed under reduced pressure and the residue was dissolvedin DCM (100 mL) and neutralized using aqueous 2 N NaOH. Saturatedaqueous NaHCO₃ (50 mL) was added and the layers were separated. Theorganic layer was washed with brine (50 mL), dried over anhydrous MgSO₄,filtered, and concentrated under reduced pressure. The crude materialwas purified by silica gel chromatography eluting with a gradient of20-80% EtOAc/heptane to afford (R)-1-tert-butyl 3-methyl4-methylpiperazine-1,3-dicarboxylate (1.1 g, 85%): LC/MS (Table 2,Method a) R_(t)=1.91 min; MS m/z: 259 (M+H)⁺.

Step B: Lithium(R)-4-(tert-butoxycarbonyl)-1-methylpiperazine-2-carboxylate

To a solution of (R)-1-tert-butyl 3-methyl4-methylpiperazine-1,3-dicarboxylate (1.2 g, 4.6 mmol) in 1,4-dioxane(18 mL) and water (18 mL) was added LiOH.H₂O (0.290 g, 6.91 mmol). Afterheating at about 80° C. for about 1 h, the reaction mixture was cooledto room temperature and the solvent was removed under reduced pressure.The solid was dried in a vacuum oven at about 65° C. for about 18 h toafford lithium(R)-4-(tert-butoxycarbonyl)-1-methylpiperazine-2-carboxylate (1.46 g,quantitative): LC/MS (Table 2, Method a) R_(t)=1.17 min; MS m/z: 245(M+H)⁺.

Preparation #17:(1S,4R)-4-(tert-Butoxycarbonylamino)cyclopent-2-enecarboxylic acid

To a solution of(1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (5.0 g, 46mmol) in water (30.5 mL) was added aqueous HCl (2 M, 23.0 mL, 46.0mmol). After heating at about 80° C. for about 2 h, the reaction mixturewas cooled to ambient temperature and the solvent was removed underreduced pressure. The solid was dried in a vacuum oven at about 70° C.and used without further purification. To a solution of(1S,4R)-4-aminocyclopent-2-enecarboxylic acid hydrochloride (9.20 g,45.8 mmol) in 1,4-dioxane (15 mL) and water (18.3 mL) at about 0° C. wasadded DIEA (32.0 mL, 183 mmol). After stirring for about 5 min, asolution of di-tert-butyl dicarbonate (11.7 mL, 50.4 mmol) in1,4-dioxane (5 mL) was added. The reaction mixture was warmed to ambienttemperature and stirred for about 18 h. Solvent was removed underreduced pressure and the crude oil was dried in a vacuum oven at about65° C. for about 3 h. The crude product was purified by silica gelchromatography eluting with a gradient of 80-100% EtOAc/heptane toafford (1S,4R)-4-(tert-butoxycarbonylamino)cyclopent-2-enecarboxylicacid (5.2 g, 50% over 2 steps): LC/MS (Table 2, Method a) R_(t)=1.81min; MS m/z: 226 (M−H)⁻.

Preparation #18:(1S,2R,4S,5R)-4-(6-Tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[3.1.0]hexan-2-amine

To a solution of ethyl(1S,2R,4S,5R)-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[3.1.0]hexan-2-ylcarbamate(0.16 g, 0.34 mmol, prepared using GG from Preparation #KK.1, A fromPreparation #9 with HATU and TEA, C with TEA) in DCM (2.3 mL) was addedtrimethylsilyl iodide (0.11 mL, 0.75 mmol). After stirring at ambienttemperature for about 24 h, additional trimethylsilyl iodide (0.11 mL,0.75 mmol) was added and the reaction mixture was heated to about 40° C.for about 4 days. The reaction mixture was cooled to ambienttemperature, followed by the addition of saturated aqueous NaHCO₃ (20mL). The mixture was stirred for about 5 min and the layers wereseparated. The aqueous layer was further extracted with DCM (20 mL). Thecombined organic layers were washed with brine (20 mL), dried overanhydrous MgSO₄, filtered, and concentrated under reduced pressure toafford(1S,2R,4S,5R)-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[3.1.0]hexan-2-aminethat contained 1 molar equiv DCM (0.17 g, 100%): LC/MS (Table 2, Methoda) R_(t)=1.76 min; MS m/z: 409 (M+H)⁺.

Preparation #19: (9H-Fluoren-9-yl)methyl4-methyl-3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate

To a solution of (9H-fluoren-9-yl)methyl3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-methylpiperidine-1-carboxylate(0.627 g, 0.836 mmol, prepared using W from Preparation #20, LL, Z fromExample #8, Step A) in DCM (10 mL) was added TFA (1.50 mL, 19.5 mmol)and the resulting mixture was stirred at ambient temperature undernitrogen for about 1 h. The solution was concentrated and the residuewas partitioned between saturated aqueous NaHCO₃ (25 mL) and EtOAc (25mL). The organic phase was washed with brine (20 mL), dried overanhydrous MgSO₄, filtered, and concentrated to yield crude(9H-fluoren-9-yl)methyl4-methyl-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)acetyl)-piperidine-1-carboxylateas an amorphous brown solid. The crude material was added to 1,4-dioxane(5 mL), Lawesson's reagent (0.203 g, 0.502 mmol) was added, and theresulting suspension was heated at about 80° C. for about 20 min. Thesolvent was removed under reduced pressure and the residue was purifiedby silica gel chromatography eluting with a gradient of 0 to 1.5%MeOH/DCM to give (9H-fluoren-9-yl)methyl4-methyl-3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylateas an off-white solid (0.21 g, 40%): LC/MS (Table 2, Method a)R_(t)=2.68 min; MS m/z: 632 (M+H)⁺.

Preparation #20:1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-methylpiperidine-3-carboxylicacid

To a solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylicacid (1.50 g, 6.17 mmol, Example #13, Step G) in 1,4-dioxane (10 mL) wasadded aqueous HCl (4N in 1,4-dioxane (4.62 mL, 18.5 mmol). The reactionmixture was heated at about 60° C. for about 16 h before being allowedto cool to ambient temperature. To the mixture was added NaHCO₃ (2.07 g,24.7 mmol) and water (10.0 mL) followed by (9H-fluoren-9-yl)methyl2,5-dioxopyrrolidin-1-yl carbonate (4.16 g, 12.3 mmol). The reaction wasstirred at about 25° C. for about 16 h. The reaction was acidified toabout pH 1 with aqueous 1N HCl and was extracted with EtOAc (75 mL). Theorganic layer was washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. The productwas purified by silica gel chromatography (40 g column) eluting with agradient of 1-5% MeOH in DCM to give1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-methylpiperidine-3-carboxylicacid (0.72 g, 31%) as a clear oil: LC/MS (Table 2, Method a) R_(t)=2.44min; MS m/z: 366 (M+H)⁺.

Preparation #21:5-Cyano-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)pyridine-2-sulfonamide

To a solution of5-bromo-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)pyridine-2-sulfonamide(0.69 g, 1.1 mmol, prepared using A from(1S,3R)-3-acetamido-2,2-dimethylcyclobutanecarboxylic acid [Tetrahedron:Asymmetry 2008, 19, 302-308] and Preparation #9 with EDC, C with DIEA,JJ, N from 5-bromopyridine-2-sulfonyl chloride [Chem Impex]) in degassedDMF (1.5 mL) was added dicyanozinc (0.321 g, 2.74 mmol) followed byPd(Ph₃P)₄ (0.063 g, 0.055 mmol, Strem). The reaction was heated at about80° C. for about 16 h under a nitrogen atmosphere. The reaction mixturewas allowed to cool to ambient temperature before it was diluted withaqueous NaOH (1N, 10 mL) and extracted with EtOAc (25 mL). The organiclayer was washed with brine (20 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The product waspurified by silica gel chromatography (12 g) eluting with a gradient of1-10% MeOH in DCM to give5-cyano-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)pyridine-2-sulfonamide(0.09 g, 14%) as a tan solid: LC/MS (Table 2, Method a) R_(t)=2.14 min;MS m/z: 577 (M+H)⁺.

Preparation #22: 2-Acetylamino-5-carboxyadamantane

To E-2-amino-5-carboxyadamantane methyl ester hydrochloride (1.0 g, 4.1mmol, as prepared in Org. Process Res. Dev., 2008, 12 (6), 1114-1118)and DIEA (2.13 mL, 12.2 mmol) in 1,4-dioxane (15 mL) was added Ac₂O(0.576 mL, 6.10 mmol). The reaction was stirred at about 25° C. forabout 3 h before the addition of aqueous NaOH (2N, 8.14 mL, 16.3 mmol).The reaction was stirred at about 25° C. for about 16 h before it waspartitioned between EtOAc (100 mL) and aqueous 1 N HCl (50 mL). Theorganic layer was washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure to give2-acetylamino-5-carboxyadamantane (0.47 g, 49%) as a white solid: LC/MS(Table 2, Method a) R_(t)=1.43 min; MS m/z: 236 (M−H)⁻.

Preparation #23: 6-Fluoro-4-methylnicotinamide

A round bottom flask was charged with 6-fluoro-4-methylnicotinic acid(1.13 g, 7.28 mmol, Frontier) and DCM (73 mL) to give a clear solution,Thionyl chloride (5.32 mL, 72.8 mmol) was added drop-wise and themixture was stirred at room temperature overnight. The reaction mixturewas concentrated to dryness under reduced pressure and the residue wasdissolved in EtOAc (10 mL) and added drop-wise to a rapidly stirredmixture of EtOAc (40 mL) and concentrated aqueous NH₄OH (36.9 ml, 947mmol). The mixture was stirred for about 1 h, and the layers wereseparated. The aqueous layer was further extracted with EtOAc (50 mL)and the combined extracts were washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness under reduced pressure togive 6-fluoro-4-methylnicotinamide (0.69 g, 61%) as white solid: LC/MS(Table 2, Method d) R_(t)=1.03 min; MS m/z 153 (M−H)⁻.

Preparation #24: 1-(5-Tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanaminehydrochloride

Step A: 1-(5-Tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanol

To a solution of methylmagnesium chloride (0.232 mL, 0.697 mmol) in THF(10 mL) at about −78° C. was added a solution of5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (0.210 g, 0.697 mmol,Example #10, Step B) in DCM (10.0 mL). After about 10 min saturatedaqueous NH₄Cl was added to the reaction mixture. After warming to roomtemperature, EtOAc (30 mL) was added to the reaction mixture and theorganic layer was separated, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude material was purified bysilica gel chromatography eluting with 20-80% EtOAc/heptane to provide1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanol (0.050 g, 23%) as ayellow oil. LC/MS (Table 2, Method a) R_(t)=2.04 min; MS m/z: 318(M+H)⁺.

Step B: 2-(1-Azidoethyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanol (0.600g, 1.89 mmol) in DCM (10 mL) was added SOCl₂ (0.690 mL, 9.45 mmol) atambient temperature. After about 4 h the reaction mixture was dilutedwith EtOAc (50 mL) and saturated aqueous NaHCO₃ (50 mL) was added to thereaction mixture. After gas evolution ceased, the organic layer wasseparated, dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was dissolved in DMF (10 mL) and sodiumazide (0.615 g, 9.45 mmol) was added to the reaction mixture. Afterabout 15 h, EtOAc (50 mL) and water (50 mL) were added to the reactionmixture. The organic layer was separated, concentrated under reducedpressure, and purified by silica gel chromatography eluting with 20-80%EtOAc/heptane to provide2-(1-azidoethyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.65 g, 100%) as acolorless solid: LC/MS (Table 2, Method a) R_(t)=2.67 min; MS m/z: 343(M+H)⁺.

Step C: 1-(5-Tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanaminehydrochloride

To a solution of 2-(1-azidoethyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine(0.65 g, 1.9 mmol) in THF (10 mL) and water (5 mL) was addedtriphenylphosphine (0.598 g, 2.28 mmol). The reaction mixture was heatedto about 45° C. and after about 12 h the reaction mixture was cooled toroom temperature and concentrated under reduced pressure. The residuewas dissolved in EtOAc (40 mL) and HCl gas was passed through thesolution until pH of 1. Et₂O (40 mL) was slowly added and the solventwas decanted away from the resulting solid. The solid was dried undervacuum to provide 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanaminehydrochloride (0.65 g, 97%) as a tan solid: LC/MS (Table 2, Method a)R_(t)=1.56 min; MS m/z: 317 (M+H)⁺.

Preparation #25: 2,2-Dimethyl-4-oxocyclopentanecarboxylic acid

To a solution of 4,4-dimethylcyclopent-2-enone (2.0 g, 18 mmol) in EtOH(50 mL), water (7.5 mL) and AcOH (1.5 mL) was added potassium cyanide(2.36 g, 36.3 mmol). The reaction mixture was heated to about 40° C. andafter about 15 h the reaction mixture was concentrated under reducedpressure. The residue was diluted with EtOAc (50 mL) and washed withbrine. The organic layer was separated, dried over anhydrous Na₂SO₄,filtered, and concentrated. The residue was dissolved in aqueous HCl(6N, 50 mL) and heated to reflux. After about 3 days the reactionmixture was cooled to room temperature and concentrated under reducedpressure to provide 2,2-dimethyl-4-oxocyclopentanecarboxylic acid (3.7g, 90%, ˜70% purity by ¹H NMR) that was carried on without additionalpurification: LC/MS (Table 2, Method a) R_(t)=1.30 min; MS m/z: 155(M−H)⁻.

Preparation #26:4-(tert-Butoxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylic acid

Step A: 4-(Methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid

To a solution of dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate (2.00g, 9.44 mmol, as prepared in Aust. J. Chem., 1985, 38, 1705-18) in MeOH(47 mL) was added KOH (0.475 g, 8.46 mmol) and water (2.5 mL). Thereaction was stirred at reflux for about 16 h and then cooled to roomtemperature and concentrated to dryness under reduced pressure. Water(25 mL) was added to the remaining residue and the mixture was extractedwith Et₂O (2×25 mL). The aqueous layer was acidified to about pH 4 usingaqueous 6 N HCl and was extracted with DCM (3×20 mL). The combined DCMextracts were dried over anhydrous MgSO₄, filtered, and concentrated toprovide 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid as anoff-white solid (1.19 g, 71%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.19 (s,1H), 3.61 (s, 3H), 1.92 (d, J=6.6 Hz, 4H), 1.76 (s, 2H), 1.65-1.54 (m,4H).

Step B: Methyl4-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylate

To a solution of 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylicacid (2.01 g, 10.1 mmol) in toluene (30 mL) was added diphenylphosphoryl azide (2.20 mL, 10.2 mmol) and TEA (1.60 mL, 11.5 mmol). Themixture was stirred at room temperature for about 1 h followed byheating at about 50° C. for about 3 h and further heating at about 70°C. for about 2 h. The reaction was cooled to room temperature andconcentrated to dryness under reduced pressure. The residue was dilutedin tert-butanol (10.0 mL, 105 mmol) and the mixture was heated at about80° C. for about 16 h. The reaction mixture was cooled to roomtemperature and dissolved in Et₂O (50 mL). The organic layer was washedwith water, aqueous 1 M NaOH, water, and brine (25 mL each). The organiclayer was dried over anhydrous Na₂SO₄, filtered, and concentrated toprovide methyl4-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylate as anoff-white solid (2.22 g, 81%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.03 (s, 1H),3.59 (s, 3H), 1.95-1.74 (m, 6H), 1.60 (s, 4H), 1.37 (s, 9H).

Step C: 4-(tert-Butoxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylicacid

To a solution of methyl4-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylate (2.21 g,8.20 mmol) in THF (27 mL) and MeOH (14 mL) was added aqueous NaOH (1 N,20.0 mL, 20.0 mmol). The mixture was stirred at room temperature forabout 16 h and concentrated to dryness under reduced pressure. Water (25mL) was added to the remaining residue and the mixture was extractedwith Et₂O (2×25 mL) and the Et₂O extracts were discarded. The aqueouslayer was acidified to about pH 4 using aqueous 6 N HCl and extractedwith Et₂O (3×10 mL). The combined organic layers were dried overanhydrous MgSO₄, filtered, and concentrated to dryness under reducedpressure to provide4-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylic acid asan off-white solid (1.69 g, 81%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s,1H), 7.00 (s, 1H), 2.00-1.69 (m, 6H), 1.67-1.45 (m, 4H), 1.37 (s, 9H).

Preparation #27: 6-Chloro-4-(trifluoromethyl)nicotinamide

6-Chloro-4-(trifluoromethyl)nicotinic acid (1.0 g, 4.4 mmol, Oakwood)was dissolved in DCM (44 mL) to give a clear solution, SOCl₂ (3.2 mL, 44mmol) was added drop-wise and the reaction mixture was stirred at roomtemperature overnight and then at reflux for about 16 h. The mixture wasconcentrated under reduced pressure to give a yellow oil that wasdissolved into EtOAc (10 mL). The solution was added drop-wise to arapidly stirred mixture of EtOAc (20 mL) and concentrated aqueous NH₄OH(22 mL, 580 mmol). The resulting cloudy mixture was stirred for about 2h and separated. The aqueous layer was further extracted with EtOAc (30mL). The combined organic extracts were washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure togive 6-chloro-4-(trifluoromethyl)nicotinamide (0.85 g, 85%) as off-whitesolid: LC/MS (Table 2, Method a) R_(t)=1.62 min; MS m/z: 223 (M+H)⁺.

Preparation #28: (5-Tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanaminehydrochloride

A 5-L reactor was charged with 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine(98.8 g, 281 mmol, Preparation #7), zinc dust (3.50 g, 53.3 mmol),palladium (II) trifluoroacetate (4.0 g, 12 mmol), andracemic-2-(di-t-butylphosphino)-1,1′-binapthyl (9.8 g, 24.7 mmol). Theflask was equipped with a powder addition device into which zinc cyanide(10.0 g, 157 mmol) was placed to be added at a later step. The vesselwas purged with argon for no longer than about 30 min and then argonsparged DMA (2 L) was added to the reactor. The mixture was stirred andheated to about 50° C. while maintaining an argon sparge. The resultingdark brown solution was further heated to about 95° C. while adding thezinc cyanide, from the powder addition device, portion-wise over about15 min. Upon reaching about 95° C., the brown mixture is stirred forabout an additional 16 h. The reaction mixture was cooled to roomtemperature, resulting in the precipitation of salts. The mixture wasfiltered through a Buchner funnel containing filter-aid and the filtercake was washed with DMA (20 mL). A solution of the crude product in DMAwas added to cold (<10° C.) water (16 L) and stirred for about 30 min.The resulting suspension was filtered and the filter cake was rinsedagain with water (1 L). The resulting wet cake was dried in a vacuumoven at about 50° C. The crude solid was dissolved in DCM (1.5 L) andfurther dried over anhydrous MgSO₄. After filtration, the solution waspassed through a pad of silica (140 g), washing with additional solventuntil only predominantly impurities were detected eluting off the pad.The solvent was removed and the crude solid was triturated with MeOH/DCM(4:1, 10 volumes of solvent per gram of crude solid) at ambienttemperature for about 5 h. The solid was filtered and washed with MeOH(300 mL). The product was dried in a vacuum oven to provide5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (58.8 g, 70%) as acolorless solid: ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 8.21 (d, J=4.2Hz, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 6.89 (d, J=4.2Hz, 1H), 2.42 (s, 3H). A 2-L 316-stainless steel pressure reactor wascharged with 5% Pd/C (15.4 g of 63.6 wt % water wet material, 5.6 g drybasis, Johnson Matthey A503032-5),5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (55 g, 184 mmol), THF(1.1 L), deionized water (165 mL), aqueous HCl, (37 wt %, 30 mL, 369mmol) and quinoline (1.1 mL, 9.0 mmol). The vessel was purged,pressurized, and maintained at 40 psi with hydrogen supplied from a highpressure reservoir. The mixture was vigorously agitated at about 25° C.After about 5 h the reactor was vented and purged with nitrogen toremove most of the dissolved hydrogen, and the reaction mixture wasfiltered to remove the catalyst. The reactor and catalyst cake wererinsed with THF:H₂O (1:1, 2×40 mL). The combined filtrate and rinseswere concentrated and EtOH (500 mL) was added. After two additionalsolvent switches with EtOH (2×500 mL), the crude residue wasconcentrated to give a residue (76 g) that was suspended in EtOH (550mL) and stirred at ambient temperature for about 4 h. The solid wascollected by filtration and washed with cold EtOH (50 mL). The wet cakewas dried in a vacuum oven to provide(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (51.2g, 82%) as a colorless solid: LC/MS (Table 2, Method a) R_(t)=1.44 min;MS m/z: 303 (M+H)⁺.

General Procedure A: Formation of a Hydrazide from a Carboxylic Acid

To mixture of a 2-hydrazinylpyrrolo[2,3-b]pyrazine (preferably 1 equiv)and a carboxylic acid (1-2 equiv, preferably 1.1-1.3 equiv) in a solventsuch as DCM or THF, preferably DCM, is added a coupling agent such asEDC.HCl or HATU (1.0-2.0 equiv, preferably 1.2-1.6 equiv) with orwithout an organic base such as TEA or DIEA (2-5 equiv, preferably 3-4equiv). After about 1-72 h (preferably 2-6 h) at about 20-60° C.(preferably about room temperature), the reaction is worked up using oneof the following methods. Method 1: Water is added and the layers areseparated. Optionally, the mixture may be filtered through Celite® priorto the separation of the layers. The aqueous layer is then extractedwith an organic solvent such as EtOAc or DCM. The combined organiclayers are optionally washed with brine, dried over anhydrous Na₂SO₄ orMgSO₄, filtered or decanted, and concentrated under reduced pressure.Method 2: The reaction is diluted with an organic solvent such as EtOAcor DCM and is washed with either water or brine or both. The aqueouslayer is optionally further extracted with an organic solvent such asEtOAc or DCM. Then the organic layer or combined organic layers areoptionally washed with brine, dried over anhydrous Na₂SO₄ or MgSO₄,filtered or decanted, and concentrated under reduced pressure. Method 3:The reaction is diluted with an organic solvent such as EtOAc or DCM andwater is added. The layers are separated and the organic layer isdirectly purified by chromatography. In all cases, the crude material isoptionally purified by precipitation, crystallization, and/ortrituration from an appropriate solvent or solvents and/or bychromatography to give the target compound.

Illustration of General Procedure A

Preparation #A.1: tert-Butyl(1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate

To mixture of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.50 g,8.24 mmol, Preparation #9) and(1R,3S)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (2.08 g,9.07 mmol, Peptech) in DCM (30 mL) was added EDC.HCl (1.90 g, 9.89mmol). After about 4.5 h at ambient temperature, water (30 mL) was addedand the layers were separated. The aqueous layer was then extracted withEtOAc (15 mL). The combined organic layers were washed with brine, driedover anhydrous MgSO₄, filtered, and concentrated under reduced pressure.The crude material was dissolved in DCM (15 mL) and purified by silicagel chromatography eluting with a gradient of 40-100% EtOAc in heptaneto give tert-butyl(1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate(4.20 g, 97%): LC/MS (Table 2, Method a) R_(t)=2.27 min; MS m/z: 515(M+H)⁺.

General Procedure B: Formation of a Hydrazide from an Acid ChlorideFollowed by Cyclization and Sulfonamide Hydrolysis

To a solution of 5-sulfonyl-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine(preferably 1 equiv) and TEA or DIEA (1-10 equiv, preferably 4 equiv) in1,4-dioxane at about 0-25° C. (preferably ambient temperature) is addedan acid chloride (1-1.5 equiv, preferably 1 equiv). After the completeaddition, the reaction is allowed to warm to ambient temperature ifcooled initially. After about 0.5-2 h (preferably about 1 h), SOCl₂(1-10 equiv, preferably 3 equiv) is added and the reaction is heated atabout 60-100° C. (preferably about 80-90° C.) for about 0.25-8 h(preferably about 1 h). The reaction is allowed to cool to ambienttemperature and then aqueous base (such as aqueous Na₂CO₃ or aqueousNaOH, preferably aqueous NaOH) is added followed by the optional, butnot preferable, addition of MeOH (5-50% of the reaction volume,preferably 50%). The reaction is heated at about 50-90° C. for about1-96 h (preferably about 3 h at about 60° C. if using aqueous NaOH orabout 3 days at about 90° C. if using aqueous Na₂CO₃). The reaction isconcentrated under reduced pressure and then is partitioned between anorganic solvent (such as EtOAc or DCM, preferably EtOAc) and water,saturated aqueous NaHCO₃ and/or brine, preferably saturated aqueousNaHCO₃. The organic layer is separated and optionally washed with waterand/or brine, dried over anhydrous Na₂SO₄ or MgSO₄, filtered ordecanted, and concentrated under reduced pressure. The crude material isoptionally purified by precipitation, crystallization, and/ortrituration from an appropriate solvent or solvents and/or bychromatography to give the target compound.

Illustration of General Procedure B

Example #B.1.11-(2-Methylcyclohexyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a solution of5-(4-tert-butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine(0.40 g, 1.2 mmol, Preparation #3) and DIEA (0.20 mL, 1.2 mmol) in1,4-dioxane (12 mL) at about 0° C. was added 2-methylcyclohexanecarbonylchloride (0.19 g, 1.2 mmol, Preparation #4). After the completeaddition, the ice bath was removed and the reaction was allowed to warmto ambient temperature. After about 1 h, SOCl₂ (0.42 mL, 5.8 mmol) wasadded and the reaction was heated at about 90° C. for about 1 h. Thereaction was allowed to cool to ambient temperature and then 2 M aqueousNa₂CO₃ (2N, 11.6 mL, 23.2 mmol) and MeOH (12 mL) were added. Thereaction was heated at about 90° C. for about 3 days. The reaction wasconcentrated under reduced pressure and then partitioned between EtOAc(50 mL) and saturated aqueous NaHCO₃ (40 mL). The organic layer wasseparated and dried over anhydrous Na₂SO₄, filtered and the solvent wasconcentrated under reduced pressure. The residue was purified oversilica gel (12 g) using EtOAc as the eluent and then further purified byRP-HPLC (Table 2, Method b). The combined product-containing fractionswere concentrated under reduced pressure to remove the MeCN and theresulting precipitate was collected by vacuum filtration to afford1-(2-methylcyclohexyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineas a white solid (0.10 g, 35%): LC/MS (Table 2, Method a) R_(t)=1.84min; MS m/z: 256 (M+H)⁺.

General Procedure C: Cyclization of a Hydrazide

To a solution of a 2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine (preferably 1equiv) in an organic solvent (for example 1,4-dioxane) is added a basesuch as TEA or DIEA (1-5 equiv, preferably 2-4 equiv) and SOCl₂ (1-5equiv, preferably 1-2 equiv). The mixture is heated at about 60-100° C.(preferably about 80° C.) for about 1-16 h (preferably about 1-2 h). Thereaction mixture is cooled to ambient temperature and worked up usingone of the following methods. Method 1: An organic solvent (such asEtOAc or DCM) and water are added. The layers are separated and theaqueous layer is optionally extracted with additional organic solvent.The combined organic layers may be optionally washed with aqueous base(such as NaHCO₃) and/or brine, dried over anhydrous Na₂SO₄ or MgSO₄,then decanted or filtered prior to concentrating under reduced pressure.Method 2: An organic solvent (such as EtOAc or DCM) is added and theorganic layer is optionally washed with brine or water, dried overanhydrous MgSO₄ or Na₂SO₄, filtered or decanted, and concentrated underreduced pressure. Method 3: The reaction mixture is partitioned betweenan organic solvent (such as EtOAc or DCM) and saturated aqueous NaHCO₃or brine, dried over anhydrous Na₂SO₄ or MgSO₄, then decanted orfiltered prior to concentrating under reduced pressure. The crudematerial is optionally purified by precipitation, crystallization,and/or trituration from an appropriate solvent or solvents and/or bychromatography to give the target compound.

Illustration of General Procedure C

Preparation #C.1:tert-Butyl-(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate

To a solution of tert-butyl(1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate(9.30 g, 18.1 mmol, Preparation #A.1) in 1,4-dioxane (100 mL) was addedTEA (10.0 mL, 72.3 mmol) and SOCl₂ (2.11 mL, 28.9 mmol). The mixture washeated at about 80° C. for about 1.5 h. The reaction mixture was cooledto ambient temperature, EtOAc and water (200 mL each) were added, andthe layers were separated. The aqueous solution was extracted with EtOAc(2×100 mL) and the combined organic layers were washed with saturatedaqueous NaHCO₃ and brine (100 mL each). The organic extracts were driedover anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. The crude material was purified by silica gel chromatographyeluting with a gradient of 25-100% EtOAc in DCM to givetert-Butyl-(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1, 2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate (7.65 g, 85%): LC/MS(Table 2, Method a) R_(t)=2.37 min; MS m/z: 497 (M+H)⁺.

General Procedure D: Cyclization of a Hydrazide Followed by SulfonamideHydrolysis and Boc-Deprotection

A round-bottomed flask is charged with a5-sulfonyl-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine (preferably 1 equiv),an organic solvent (such as 1,4-dioxane or THF, preferably 1,4-dioxane),SOCl₂ (2-5 equiv, preferably 2 equiv) and an organic base such as DIEAor TEA (0-5 equiv, preferably 3 equiv). The resulting mixture is stirredat about 25-120° C. (preferably about 90° C.) for about 0.25-5 h(preferably about 1 h) and then allowed to cool to ambient temperature.To the reaction mixture is added an aqueous base (such as aqueous Na₂CO₃or aqueous NaOH, 1-30 equiv, preferably 1-2 equiv for aqueous NaOH,preferably 15-20 equiv for aqueous Na₂CO₃) and the resulting mixture isheated at about 60-120° C. (preferably about 90° C.) for about 1-10 h(preferably about 5 h) then allowed to cool to ambient temperature. MeOH(5-50% of the reaction volume, preferably 20-30%) is added to thereaction mixture and the resulting solution is heated at about 60-120°C. (preferably about 90° C.) for about 5-24 h (preferably about 16 h)and then allowed to cool to ambient temperature. The layers areseparated and the organic solvent is concentrated under reducedpressure. To the residue is added an organic solvent (such as1,4-dioxane or THF, preferably 1,4-dioxane) followed by a solution ofHCl, such as 4 M HCl in 1,4-dioxane (20-40 equiv, preferably 25 equiv).The resulting suspension is stirred at about 20-80° C. (preferably about60° C.) for about 1-16 h (preferably about 1 h) and then allowed to coolto ambient temperature. The solid is collected by vacuum filtration,washed with organic solvent (such as 1,4-dioxane, EtOAc and/or Et₂O,preferably 1,4-dioxane followed by Et₂O) to yield the crude product asan HCl salt. The crude material is optionally purified by precipitation,crystallization, or trituration from an appropriate solvent or solventsor by chromatography to give the target compound.

Illustration of General Procedure D

Example #D.1.1cis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanaminehydrochloride andcis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanamine

A round-bottomed flask was charged withcis-tert-butyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclohexylcarbamate(0.415 g, 0.785 mmol, prepared using A fromcis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid [AMRI] andPreparation #9), 1,4-dioxane (9 mL) and SOCl₂ (0.115 mL, 1.57 mmol). Theresulting mixture was heated at about 90° C. for about 1 h and thenallowed to cool to ambient temperature. To the reaction mixture wasadded aqueous Na₂CO₃ (5 N, 7.85 mL, 15.7 mmol) and the reaction mixturewas heated at about 90° C. for about 5 h. MeOH (5 mL) was added to thereaction mixture and the resulting mixture was heated at about 90° C.for about 16 h and then allowed to cool to ambient temperature. Thelayers were separated and the organic layer was concentrated underreduced pressure. To the residue was added 1,4-dioxane (10 mL) followedby HCl (4 M in 1,4-dioxane, 5 mL, 20.0 mmol). The resulting suspensionwas heated at about 60° C. for about 1 h and then allowed to cool toambient temperature. The solid was collected by vacuum filtration,washed first with 1,4-dioxane (1 mL) then Et₂O (50 mL) to yield thecrude productcis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanaminehydrochloride (0.42 g, 98%, 84% purity). A portion of the crude HCl salt(0.075 g) was further purified by RP-HPLC (Table 2, Method g) to givecis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanamine(0.044 g) with 3 equiv NH₄OAc as an excipient. LC/MS (Table 2, Method a)R_(t)=0.92 min; MS m/z: 257 (M+H)⁺.

TABLE D.1 Examples prepared using General Procedure D: R_(t) min (Table2, m/z ESI+ Hydrazide Product Example # Method) (M + H)⁺ tert-Butyl(1R,3S)-3-(2-(5-tosyl-5H- (1R,3S)-3-(6H- D.1.2 0.47 (d) 243pyrrolo[2,3-b]pyrazin-2- Pyrrolo[2,3-yl)hydrazinecarbonyl)cyclopentylcarbamate e][1,2,4]triazolo[4,3-(prepared using A from (1S,3R)-3- a]pyrazin-1-yl)cyclo- (tert-pentanamine butoxycarbonylamino)cyclopentanecarboxylic hydrochlorideacid [PepTech] and Preparation #9) tert-Butyl trans-4-(2-(5-tosyl-5H-trans-4-(6H- D.1.3 0.44 (d) 257 pyrrolo[2,3-b]pyrazin-2- Pyrrolo[2,3-yl)hydrazinecarbonyl)cyclohexylcarbamate e][1,2,4]triazolo[4,3-(prepared using A from trans-4- a]pyrazin-1-yl)cyclo- (tert- hexanaminebutoxycarbonylamino)cyclohexanecarboxylic hydrochloride acid [AMRI] andPreparation #9) tert-Butyl (1R,3R)-3-(2-(5-(4-tert- (1R,3R)-3-(6H- D.1.40.46 (d) 243 butylphenylsulfonyl)-5H-pyrrolo[2,3- Pyrrolo[2,3-b]pyrazin-2- e][1,2,4]triazolo[4,3-yl)hydrazinecarbonyl)cyclopentylcarbamate a]pyrazin-1-yl)cyclo-(prepared using A from (1S,3S)-3- pentanamine (tert- hydrochloridebutoxycarbonylamino)cyclopentanecarboxylic acid [Acros] and Preparation#3)General Procedure E: Cyclization of a Hydrazide Followed by SulfonamideHydrolysis

To a solution of a 5-sulfonyl-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine(preferably 1 equiv) in a solvent such as 1,4-dioxane is added SOCl₂(1-5 equiv, preferably 1-2 equiv). Optionally, an organic base, such asTEA or DIEA, (1-5 equiv, preferably 2-4 equiv) is added before SOCl₂,particularly for Boc-protected substrates. The reaction is heated atabout 60-100° C. (preferably about 80° C.). After about 0.5-6 h(preferably about 1-2 h), an aqueous base (such as aqueous Na₂CO₃ oraqueous NaOH, 1-90 equiv, preferably 15-20 equiv for aqueous Na₂CO₃ or1-2 equiv for aqueous NaOH), is added and heating is resumed at about60-90° C. (preferably about 80° C.) for about 1-72 h (preferably about1-16 h). Optionally, but not preferably, the reaction is cooled toambient temperature for a period of time (5 min-72 h), during which timeMeOH and/or additional aqueous base (such as saturated Na₂CO₃ or 1 NNaOH) may be added, and heating is optionally resumed at about 60-90° C.(preferably about 80° C.) for about 1-72 h (preferably about 1-16 h).This cycle of optionally cooling to ambient temperature and adding basemay occur up to four times. The reaction is worked up using one of thefollowing methods. Method 1: An organic solvent such as EtOAc or DCM isadded with the optional addition of water, brine, or saturated aqueousNH₄Cl (preferably water) and the layers are separated. The aqueous layeris then optionally extracted with additional organic solvent such asEtOAc or DCM. The combined organic layers are optionally washed withbrine or water, dried over anhydrous MgSO₄ or Na₂SO₄, filtered ordecanted, and concentrated under reduced pressure. Method 2: Thereaction mixture is decanted and the insoluble material is washed withan organic solvent such as EtOAc. The combined organic layers areconcentrated under reduced pressure. Method 3: The reaction mixture isconcentrated under reduced pressure to remove solvent. Water is addedand the aqueous layer is extracted with an organic solvent such as EtOAcor DCM. The combined organic layers are optionally washed with brine orwater, dried over anhydrous MgSO₄ or Na₂SO₄, filtered or decanted, andconcentrated under reduced pressure. Method 4: A reaction mixturecontaining a precipitate may be filtered to collect the target compound,while optionally washing with water. The filtrate may be optionallyconcentrated and purified to yield additional target compound. Method 5:The reaction mixture is adjusted to neutral pH with the addition of asuitable aqueous acid (such as aqueous HCl) prior to extraction with anorganic solvent such as EtOAc or DCM. The combined organic layers areoptionally washed with brine or water, dried over anhydrous MgSO₄ orNa₂SO₄, filtered or decanted, and concentrated under reduced pressure.In all cases, the crude material is optionally purified byprecipitation, crystallization, and/or trituration from an appropriatesolvent or solvents and/or by chromatography to give the targetcompound.

Illustration of General Procedure E

Example #E.1 tert-Butyl(1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate

To a solution of tert-butyl(1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate(4.73 g, 9.19 mmol, Preparation #A.1) in 1,4-dioxane (50 mL) was addedTEA (5.10 mL, 36.8 mmol) and SOCl₂ (1.34 mL, 18.4 mmol). The reactionmixture was heated at about 80° C. After about 1.5 h, saturated aqueousNa₂CO₃ (100 mL) was added and heating was resumed at about 80° C. forabout 6 h. The reaction was cooled to ambient temperature for about 3days and then heated at about 80° C. for about 16 h. Water and EtOAc(100 mL each) were added and the layers were separated. The aqueouslayer was then extracted with additional EtOAc (2×100 mL). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The crude solid wastriturated with petroleum ether (b.p. 30-60° C.; 30 mL) and collected byvacuum filtration, while washing with additional petroleum ether (b.p.30-60° C.; 20 mL), to give tert-butyl(1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamateas a light brown solid (2.86 g, 86%): LC/MS (Table 2, Method a)R_(t)=1.75 min; MS m/z: 343 (M+H)⁺.

TABLE E.1 Examples prepared using General Procedure E R_(t) min m/z ESI+Hydrazide Product Ex # (Table 2, Method) (M + H)⁺Adamantane-2-carboxylic acid N′- 1-Adamantan-2-yl- E.1.1 2.09 (a) 294[5-(4-tert-butyl-benzenesulfonyl)- 6H-pyrrolo [2,3-5H-pyrrolo[2,3-b]pyrazin-2-yl]- e][1,2,4]triazolo[4,3- hydrazide(prepared using A from a]pyrazine Preparation #3 and adamantane-2-carboxylic acid [Enamine]) Adamantane-1-carboxylic acid N′-1-Adamantan-1-yl- E.1.2 2.01 (a) 294 [5-(4-tert-butyl-benzenesulfonyl)-6H-pyrrolo [2,3- 5H-pyrrolo[2,3-b]pyrazin-2-yl]- e][1,2,4]triazolo[4,3-hydrazide (prepared using A from a]pyrazine Preparation #3 andadamantane-1- carboxylic acid, EDC•HCl, and TEA) Benzyl(1S,3S)-3-(2-(5-tosyl-5H- Benzyl (1S,3S)-3- E.1.3 1.85 (a) 363pyrrolo[2,3-b]pyrazin-2- (6H-pyrrolo[2,3-yl)hydrazinecarbonyl)cyclobutylcarbamate, e][1,2,4]triazolo[4,3-(prepared using Q from 3- a]pyrazin-1- aminocyclobutanecarboxylic acidyl)cyclobutylcarbamate hydrochloride (Enamine) and A from Preparation#9) 4-Methoxy-N′-(5-tosyl-5H- 1-(4- E.1.4 1.56 (a) 272pyrrolo[2,3-b]pyrazin-2- Methoxycyclohexyl)-yl)cyclohexanecarbohydrazide, 6H-pyrrolo[2,3- (prepared using A from 4-e][1,2,4]triazolo[4,3- methoxycyclohexanecarboxylic acid a]pyrazine andPreparation #9)General Procedure F: Cyclization of a Hydrazide with Loss ofBoc-Protecting Group Followed by Sulfonamide Hydrolysis

To a solution of a 5-sulfonyl-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine(preferably 1 equiv) and TEA or DIEA (0-6 equiv, preferably 1 equiv) in1,4-dioxane is added SOCl₂ (2.0-6.0 equiv, preferably 3 equiv). Thereaction is heated at about 60-120° C. (preferably about 80-90° C.) forabout 1-8 h (preferably about 1-4 h). The reaction is allowed to cool toambient temperature then is optionally, but not preferably, diluted witha cosolvent (such as MeOH or EtOH, preferably MeOH) by 5-50% of thereaction volume (preferably 50%). An aqueous base (such as aqueousNa₂CO₃ or aqueous NaOH, 1-30 equiv, preferably 1-2 equiv for aqueousNaOH, preferably 15-20 equiv for aqueous Na₂CO₃) is added and thereaction is heated at about 40-90° C. (preferably about 60° C.) forabout 1-24 h (preferably about 2 h) before it is concentrated underreduced pressure. The crude material is optionally purified byprecipitation, precipitation by salt formation, crystallization, and/ortrituration from an appropriate solvent or solvents and/or bychromatography to give the target compound.

Illustration of General Procedure F

Example #F.1.1((1R,3R)-3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanaminehydrochloride

To a solution oftert-butyl((1R,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)methylcarbamate(0.60 g, 1.1 mmol, prepared using A from(1R,3R)-3-((tert-butoxycarbonylamino)methyl)cyclopentanecarboxylic acid[AFID] and Preparation #9) and DIEA (0.79 mL, 4.5 mmol) in 1,4-dioxane(5 mL) was added SOCl₂ (0.166 mL, 2.27 mmol). The reaction mixture washeated at about 80° C. for about 1 h before it was allowed to cool toambient temperature. Aqueous NaOH (2 N, 4 mL, 8 mmol) was added to thereaction mixture and heated at about 60° C. for about 2 h. The reactionmixture was allowed to cool to ambient temperature before it wasconcentrated under reduced pressure. To the residue was added HCl (4N in1,4-dioxane (20 mL). The organic solution was decanted away from theresulting precipitate to afford((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanaminehydrochloride as a yellow solid (0.11 g, 33%): LC/MS (Table 2, Method a)R_(t)=1.01 min; MS m/z: 257 (M+H)⁺.

TABLE F.1 Examples prepared using General Procedure F R_(t) min (Table2, m/z ESI+ Hydrazide Product Ex # Method) (M + H)⁺tert-Butyl-trans-3-(2-(5-(4-tert- trans-3-(6H- F.1.2 1.07 (a) 257butylphenylsulfonyl)-5H-pyrrolo[2,3- Pyrrolo[2,3- b]pyrazin-2-e][1,2,4]triazolo[4, yl)hydrazinecarbonyl)cyclohexylcarbamate3-a]pyrazin-1- (prepared using A from Preparation yl)cyclohexanamine #3and trans-3-(tert-butoxycarbonyl- acetate amino)cyclohexanecarboxylicacid [AMRI], EDC•HCl, and TEA) tert-Butyl-cis-3-(2-(5-(4-tert-cis-3-(6H- F.1.3 1.18 (a) 257 butylphenylsulfonyl)-5H-pyrrolo[2,3-Pyrrolo[2,3- b]pyrazin-2- e][1,2,4]triazolo[4,yl)hydrazinecarbonyl)cyclohexylcarbamate 3-a]pyrazin-1- (prepared usingA from Preparation yl)cyclohexanamine #3 and cis-3-(tert-butoxycarbonyl-hydrochloride amino)cyclohexanecarboxylic acid [AMRI], EDC•HCl, and TEA)General Procedure G: Formation of a Hydrazone Followed by Cyclizationand Sulfonamide Hydrolysis

To a solution of a 2-hydrazinyl-5-sulfonyl-5H-pyrrolo[2,3-b]pyrazine(preferably 1 equiv) in an organic solvent or solvents such as MeOH orMeOH/DCM (preferably MeOH) is added a solution of an aldehyde (1.0-1.3equiv, preferably 1.0 equiv) in an organic solvent such as DCM. Thereaction mixture is stirred at about 15-30° C. (preferably ambienttemperature) for about 1-8 h (preferably about 2 h) before iodobenzenediacetate (1-3 equiv, preferably 1 equiv) is added. The reaction isstirred at about 15-30° C. (preferably ambient temperature) for about15-60 min (preferably about 30 min) before it is concentrated toconstant weight. To the residue is added an organic solvent such as1,4-dioxane, THF, MeOH or EtOH (preferably 1,4-dioxane) followed byaqueous base such as aqueous Na₂CO₃ or NaOH (2-50 equiv), preferablyNaOH (2 equiv). The reaction was heated at about 40-80° C. (preferablyabout 60° C.) for about 1-24 h (preferably about 2 h). The crude productis optionally purified by precipitation, crystallization, and/ortrituration from an appropriate solvent or solvents and/or bychromatography to give the target compound.

Illustration of General Procedure G

Example #G.1.11-(Tetrahydro-2H-pyran-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a solution of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.100g, 0.330 mmol, Preparation #9) in MeOH (2 mL) was addedtetrahydro-2H-pyran-4-carbaldehyde (0.038 g, 0.330 mmol, J&W PharmLab)in DCM (1 mL). The reaction mixture was stirred at ambient temperaturefor about 2 h before iodobenzene diacetate (0.106 g, 0.330 mmol) wasadded. The reaction mixture was stirred at ambient temperature for about15 min before it was concentrated to constant weight. To the residue wasadded MeOH (2 mL) followed by aqueous NaOH (2 N, 0.330 mL, 0.659 mmol).The reaction mixture was heated at about 60° C. for about 1 h. The crudereaction mixture was purified by RP-HPLC (Table 2, Method f). Thecombined product-containing fractions were concentrated under reducedpressure to remove MeCN and then lyophilized to afford1-(tetrahydro-2H-pyran-4-yl)-6H-pyrrolo[2,3-e][1, 2,4]triazolo[4,3-a]pyrazine as a white solid (0.028 g, 35%): LC/MS (Table2, Method a) R_(t)=1.25 min; MS m/z: 244 (M+H)⁺.

TABLE G.1 Examples prepared from2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (Preparation #9) usingGeneral Procedure G R_(t) min (Table 2, m/z ESI+ Aldehyde Product Ex #Method) (M + H)⁺ 2,6-Dimethylcyclohex-2-1-(2,6-Dimethylcyclohex-2-enyl)- G.1.2 1.97 (a) 268 enecarbaldehyde6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine 4-(4-Hydroxy-4-5-(4-(6H-Pyrrolo[2,3- G.1.3 1.82 (a) 340 methylpentyl)cyclohex-3-e][1,2,4]triazolo[4,3-a]pyrazin-1- enecarbaldehydeyl)cyclohex-1-enyl)-2- methylpentan-2-ol Bicyclo[2.2.1]hept-5-ene-1-(Bicyclo[2.2.1]hept-5-en-2-yl)- G.1.4 1.72 (a) 252 2-carbaldehyde6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine Cyclooctanecarbaldehyde1-Cyclooctyl-6H-pyrrolo[2,3- G.1.5 2.02 (a) 270 (Oakwood)e][1,2,4]triazolo[4,3-a]pyrazine 4-o-Tolyltetrahydro-2H-1-(3-o-Tolyltetrahydro-2H-pyran- G.1.6 1.84 (a) 334 pyran-4-carbaldehyde4-yl)-6H-pyrrolo[2,3- (ASDI) e][1,2,4]triazolo[4,3-a]pyrazineBenzaldehyde 1-Phenyl-6H-pyrrolo[2,3- G.1.7 1.83 (a) 236e][1,2,4]triazolo[4,3-a]pyrazine 6-Methylcyclohex-3-1-(6-Methylcyclohex-3-enyl)-6H- G.1.8 1.83 (a) 254 enecarbaldehyde(ASDI) pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine 4-(Thiophen-2-1-(4-(Thiophen-2-yl)tetrahydro- G.1.9 1.31 (a) 326yl)tetrahydro-2H-pyran-4- 2H-pyran-4-yl)-6H-pyrrolo[2,3- carbaldehyde(ASDI) e][1,2,4]triazolo[4,3-a]pyrazine 2-(Pyridin-4-1-(2-(Pyridin-4-yl)cyclopropyl)- G.1.10 1.04 (d) 277yl)cyclopropanecarbaldehyde 6H-pyrrolo[2,3- (ASDI)e][1,2,4]triazolo[4,3-a]pyrazine p-Tolualdehyde1-p-Tolyl-6H-pyrrolo[2,3- G.1.11 1.28 (d) 250e][1,2,4]triazolo[4,3-a]pyrazine trifluoroacetateCycloheptanecarbaldehyde 1-Cycloheptyl-6H-pyrrolo[2,3- G.1.12 1.32 (d)256 e][1,2,4]triazolo[4,3-a]pyrazine trifluoroacetate2-Cycloproylacetaldehyde 1-(Cyclopropylmethyl)-6H- G.1.13 1.19 (d) 214pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine trifluoroacetate2-Cyclopentylacetaldehyde 1-(Cyclopentylmethyl)-6H- G.1.14 1.29 (d) 242pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine trifluoroacetateCyclopentanecarboxaldehyde 1-Cyclopentyl-6H-pyrrolo[2,3- G.1.15 1.24 (d)228 e][1,2,4]triazolo[4,3-a]pyrazine trifluoroacetate 3-1-(3-(Trifluoromethoxy)phenyl)- G.1.16 1.34 (d) 320(Trifluoromethoxy)benzaldehyde 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine trifluoroacetate 3,5-1-(3,5-Bis(trifluoromethyl)phenyl)- G.1.17 1.73 (1) 372Bis(Trifluoromethyl)benzaldehyde 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine trifluoroacetate o-Tolualdehyde1-o-Tolyl-6H-pyrrolo[2,3- G.1.18 1.26 (d) 250e][1,2,4]triazolo[4,3-a]pyrazine trifluoroacetate 2-1-(Quinolin-2-yl)-6H-pyrrolo[2,3- G.1.19 1.41 (1) 287Quinolinecarboxaldehyde e][1,2,4]triazolo[4,3-a]pyrazinebistrifluoroacetate 5-Methyl-2- 1-(5-Methylthiophen-2-yl)-6H- G.1.201.27 (d) 256 thiophenecarboxaldehyde pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine trifluoroacetate 4-Fluoro-2- 1-(4-Fluoro-2- G.1.21 1.31 (d)322 (trifluoromethyl)benzaldehyde (trifluoromethyl)phenyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine trifluoroacetate3,4-Dimethylbenzaldehyde 1-(3,4-Dimethylphenyl)-6H- G.1.22 1.31 (d) 264pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine trifluoroacetate4-N-Butoxybenzaldehyde 1-(4-Butoxyphenyl)-6H- G.1.23 1.40 (d) 308pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine trifluoroacetate3-Methoxybenzaldehyde 1-(3-Methoxyphenyl)-6H- G.1.24 1.25 (d) 266pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine trifluoroacetateTrimethylacetaldehyde 1-tert-Butyl-6H-pyrrolo[2,3- G.1.25 1.22 (d) 216e][1,2,4]triazolo[4,3-a]pyrazine trifluoroacetate 4-Methoxybenzaldehyde1-(4-Methoxyphenyl)-6H- G.1.26 1.24 (d) 266pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine trifluoroacetate4-Benzyloxybenzaldehyde 1-(4-(Benzyloxy)phenyl)-6H- G.1.27 1.38 (d) 342pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine trifluoroacetate 4-1-(4-(Trifluoromethyl)phenyl)-6H- G.1.28 1.34 (d) 304(Trifluoromethyl)benzaldehyde pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine trifluoroacetate 4-Phenoxybenzaldehyde1-(4-Phenoxyphenyl)-6H- G.1.29 1.38 (d) 328pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine trifluoroacetatem-Tolualdehyde 1-m-Tolyl-6H-pyrrolo[2,3- G.1.30 1.28 (d) 250e][1,2,4]triazolo[4,3-a]pyrazine trifluoroacetate 4-Ethoxybenzaldehyde1-(4-Ethoxyphenyl)-6H- G.1.31 1.29 (d) 280pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine trifluoroacetate4-N-Propoxybenzaldehyde 1-(4-Propoxyphenyl)-6H- G.1.32 1.35 (d) 294pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine trifluoroacetate4-Isopropylbenzaldehyde 1-(4-Isopropylphenyl)-6H- G.1.33 1.56 (l) 278pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine trifluoroacetate4-Acetamidobenzaldehyde N-(4-(6H-pyrrolo[2,3- G.1.34 1.16 (d) 293e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)phenyl)acetamide trifluoroacetate3- 1-(3-(Trifluoromethyl)phenyl)-6H- G.1.35 1.33 (d) 304(Trifluoromethyl)benzaldehyde pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine trifluoroacetate 3-Methylthiophene-2-1-(3-Methylthiophen-2-yl)-6H- G.1.36 1.24 (d) 256 carboxaldehydepyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine trifluoroacetateCyclopropylcarboxaldehyde 1-Cyclopropyl-6H-pyrrolo[2,3- G.1.37 1.17 (d)200 e][1,2,4]triazolo[4,3-a]pyrazine trifluoroacetate 3,3-1-Neopentyl-6H-pyrrolo[2,3- G.1.38 1.26 (l) 230 Dimethylbutyraldehydee][1,2,4]triazolo[4,3-a]pyrazine trifluoroacetate2,3-Dimethylbenzaldehyde 1-(2,3-Dimethylphenyl)-6H- G.1.39 1.29 (d) 264pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine trifluoroacetateGeneral Procedure H: Hydrolysis of a Sulfonamide

To a flask containing a sulfonamide, for example, a sulfonyl-protectedpyrrole, (preferably 1 equiv) in an organic solvent (such as1,4-dioxane, MeOH, or THF/MeOH, preferably 1,4-dioxane) is added anaqueous base (such as aqueous Na₂CO₃ or aqueous NaOH, 1-30 equiv,preferably 1-2 equiv for aqueous NaOH, preferably 15-20 equiv foraqueous Na₂CO₃). The mixture is stirred at about 25-100° C. (preferablyabout 60° C.) for about 1-72 h (preferably about 1-16 h). In cases wherethe reaction does not proceed to completion as monitored by TLC, LC/MS,or HPLC, additional aqueous base (such as aqueous Na₂CO₃, 10-20 equiv,preferably 10 equiv or aqueous NaOH, 1-5 equiv, preferably 1-2 equiv) isadded and the reaction is continued at about 25-100° C. (preferablyabout 60° C.) for about 0.25-3 h (preferably about 1-2 h). The reactionis worked up using one of the following methods. Method 1. The organicsolvent is optionally removed under reduced pressure and the aqueoussolution is neutralized with the addition of a suitable aqueous acid(such as aqueous HCl). A suitable organic solvent (such as EtOAc or DCM)and water are added, the layers are separated, and the organic solutionis dried over anhydrous Na₂SO₄ or MgSO₄, filtered, and concentrated todryness under reduced pressure to give the target compound. Method 2.The organic solvent is optionally removed under reduced pressure asuitable organic solvent (such as EtOAc or DCM) and water are added, thelayers are separated, and the organic solution is dried over anhydrousNa₂SO₄ or MgSO₄, filtered, and concentrated to dryness under reducedpressure to give the target compound. Method 3. The reaction mixture isconcentrated and directly purified by one of the subsequent methods. Thecrude material obtained from any of the preceding methods is optionallypurified by precipitation, crystallization, and/or trituration from anappropriate solvent or solvents and/or by chromatography to give thetarget compound.

Illustration of General Procedure H

Example #H.1.1N-(4-(6H-Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)-3-chlorobenzenesulfonamide

A 100 mL round-bottomed flask was charged with3-chloro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)benzenesulfonamide(0.14 g, 0.22 mmol, prepared using A from Preparation #9 and4-(tert-butoxycarbonylamino)bicyclo-[2.2.2]octane-1-carboxylic acid[Prime Organics], C with TEA, I, and N from 3-chlorobenzenesulfonylchloride) and 1,4-dioxane (5 mL) to give a tan suspension and thenaqueous NaOH (1N, 0.45 mL, 0.45 mmol, J. T. Baker) was added. Thesuspension was heated at about 60° C. for about 3 h. The reactionmixture was cooled to ambient temperature and the solvents were removedunder reduced pressure. Upon addition of NH₄OAc (50 mM aqueous buffersolution), a solid precipitated that was collected by vacuum filtration,washed with water, and dried to giveN-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)-3-chlorobenzenesulfonamideas a white solid (0.088 g, 86%): LC/MS (Table 2, Method a) R_(t)=1.88min; MS m/z: 457 (M+H)⁺.

TABLE H.1 Examples prepared using General Procedure H R_(t) min (Table2, m/z ESI+ Sulfonamide Product Ex. # Method) (M + H)⁺1-(Piperidin-1-yl)-6-tosyl-6H- 1-(Piperidin-1-yl)-6H- H.1.2 1.64 (a) 243pyrrolo[2,3-e][1,2,4]triazolo[4,3- pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (Preparation #V.1) a]pyrazine N-(4-(6-Tosyl-6H-pyrrolo[2,3-N-(4-(6H-Pyrrolo[2,3-e]- H.1.3 1.73 (a) 423e][1,2,4]triazolo[4,3-a]pyrazin-1- [1,2,4]triazolo[4,3-yl)bicyclo[2.2.2]octan-1- a]pyrazin-1- yl)benzenesulfonamide (preparedyl)bicyclo[2.2.2]octan-1-yl)benzenesulfonamide using A from Preparation#9, 4- (tert-butoxycarbonylamino)bicyclo[2.2.2]octane- 1-carboxylic acid(Prime Organics), HATU, and TEA; C with TEA; I; and N withbenzenesulfonyl chloride and TEA) 2-Cyano-N-(4-(6-tosyl-6H-N-(4-(6H-Pyrrolo[2,3- H.1.4 1.40 (a) 350pyrrolo[2,3-e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan- a]pyrazin-1- 1-yl)acetamide(prepared using A yl)bicyclo[2.2.2]octan-1- from Preparation #9,4-(tert- yl)-2-cyanoacetamide butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (Prime Organics), HATU, and TEA; C with TEA; I; and Lwith 2-cyanoacetic acid, HATU and TEA) 1-Cyano-N-(4-(6-tosyl-6H-N-(4-(6H-Pyrrolo[2,3- H.1.5 1.60 (a) 376pyrrolo[2,3-e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan- a]pyrazin-1-1-yl)cyclopropanecarboxamide yl)bicyclo[2.2.2]octan-1-yl)-1- (preparedusing A from Preparation cyanocyclopropanecarboxamide #9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane- 1-carboxylic acid (PrimeOrganics), HATU, and TEA; C with TEA; I; and L with 1-cyanocyclopropanecarboxylic acid, HATU and TEA)N-(4-(6-Tosyl-6H-pyrrolo[2,3- N-(4-(6H-Pyrrolo[2,3- H.1.6 1.52 (a) 351e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)bicyclo[2.2.2]octan-1- a]pyrazin-1- yl)cyclopropanecarboxamideyl)bicyclo[2.2.2]octan-1- (prepared using A from Preparationyl)cyclopropanecarboxamide #9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane- 1-carboxylic acid (PrimeOrganics), HATU, and TEA; C with TEA; I; and K with cyclopropanecarbonylchloride and TEA) N-(4-(6-Tosyl-6H-pyrrolo[2,3- N-(4-(6H-Pyrrolo[2,3-H.1.7 1.44 (a) 361 e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)bicyclo[2.2.2]octan-1- a]pyrazin-1-yl)methanesulfonamide (prepared yl)bicyclo[2.2.2]octan-1- using A fromPreparation #9, 4- yl)methanesulfonamide (tert-butoxycarbonylamino)bicyclo[2.2.2]octane- 1-carboxylic acid (PrimeOrganics), HATU, and TEA; C with TEA; I; and N with methanesulfonylchloride and TEA) 3-Cyano-N-(4-(6-tosyl-6H- N-(4-(6H-Pyrrolo[2,3- H.1.81.71 (a) 448 pyrrolo[2,3-e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan- a]pyrazin-1- 1-yl)benzenesulfonamide(prepared yl)bicyclo[2.2.2]octan-1- using A from Preparation #9, 4-yl)-3-cyano- (tert- benzenesulfonamidebutoxycarbonylamino)bicyclo[2.2.2]octane- 1-carboxylic acid (PrimeOrganics), HATU, and TEA; C with TEA; I; and N with 3-cyanobenzene-1-sulfonyl chloride and TEA) N-(((1S,3R)-3-(6-Tosyl-6H-N-(((1S,3R)-3-(6H- H.1.9 1.56 (a) 361 pyrrolo[2,3-e][1,2,4]triazolo[4,3-Pyrrolo[2,3- a]pyrazin-1-yl)cyclopentyl)methyl)- e][1,2,4]triazolo[4,3-cyclopropanesulfonamide (prepared a]pyrazin-1- using A from Preparation#9, yl)cyclopentyl)methyl)cyclopropanesulfonamide Preparation #P.1 andEDC•HCl; C with TEA; I; and N with cyclopropanesulfonyl chloride[Matrix]) 6-(((1S,3R)-3-(6-Tosyl-6H- 6-(((1S,3R)-3-(6H- H.1.10 1.72 (a)359 pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3-a]pyrazin-1-yl)cyclopentyl)methyl- e][1,2,4]triazolo[4,3-amino)nicotinonitrile (prepared a]pyrazin-1- using A from Preparation#9, yl)cyclopentyl)methylamino)nicotinonitrile Preparation #P.1 andEDC•HCl, C with TEA; I; and O with 6- chloronicotinonitrile)6-((1R,3S)-3-(6-Tosyl-6H- 6-((1R,3S)-3-(6H- H.1.11 1.67 (a) 345pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3-a]pyrazin-1-yl)cyclopentylamino)- e][1,2,4]triazolo[4,3- nicotinonitrile(prepared using A a]pyrazin-1- from Preparation #9, (1S,3R)-3-yl)cyclopentylamino)nicotinonitrile (tert-butoxy-carbonylamino)cyclopentane- carboxylic acid [Peptech] and EDC•HCl, Cwith TEA, I, and O with 6-chloronicotinonitrile)6-(((1S,3R)-3-(6-Tosyl-6H- N-((1R,3S)-3-(6H- H.1.12 1.51 (a) 340pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3-a]pyrazin-1-yl)cyclopentyl)methyl- e][1,2,4]triazolo[4,3-amino)nicotinonitrile (prepared a]pyrazin-1- using A from Preparation#9, yl)cyclopentyl)pyrrolidine- (1S,3R)-3-(tert-butoxy- 1-carboxamidecarbonylamino)cyclopentane- carboxylic acid [Peptech] and EDC•HCl, Cwith TEA, I, and M with pyrrolidine-1-carbonyl chloride)4-Chloro-N-(4-(6-tosyl-6H- N-(4-(6H-Pyrrolo[2,3- H.1.13 1.87 (a) 457pyrrolo[2,3-e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan- a]pyrazin-1- 1-yl)benzenesulfonamide(prepared yl)bicyclo[2.2.2]octan-1- using A from Preparation #9, 4-yl)-4- (tert- chlorobenzenesulfonamidebutoxycarbonylamino)bicyclo[2.2.2]octane- 1-carboxylic acid [PrimeOrganics], HATU, and TEA, C with TEA, I with 4N HCl in 1,4-dioxane, Nwith 4-chlorobenzene-1-sulfonyl chloride and TEA)4-Cyano-N-(4-(6-tosyl-6H- N-(4-(6H-Pyrrolo[2,3- H.1.14 1.73 (a) 448pyrrolo[2,3-e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan- a]pyrazin-1- 1-yl)benzenesulfonamide(prepared yl)bicyclo[2.2.2]octan-1- using A from Preparation #9, 4-yl)-4- (tert- cyanobenzenesulfonamidebutoxycarbonylamino)bicyclo[2.2.2]octane- 1-carboxylic acid [PrimeOrganics], HATU, and TEA, C with TEA, I with 4N HCl in 1,4-dioxane, Nwith 4-cyanobenzene-1-sulfonyl chloride [Maybridge] and TEA)3-Chloro-4-fluoro-N-(4-(6-tosyl- N-(4-(6H-Pyrrolo[2,3- H.1.15 1.90 (a)475 6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- a]pyrazin-1-yl)bicyclo[2.2.2]octan-1- yl)bicyclo[2.2.2]octan-1-yl)benzenesulfonamide (prepared yl)-3-chloro-4- using A from Preparation#9, 4- fluorobenzenesulfonamide (tert-butoxycarbonylamino)bicyclo[2.2.2]octane- 1-carboxylic acid [PrimeOrganics], HATU, and TEA, C with TEA, I with 4N HCl in 1,4-dioxane, Nwith 3-chloro-4-fluorobenzene-1- sulfonyl chloride [Lancaster] and TEA)3,4-Difluoro-N-(4-(6-tosyl-6H- N-(4-(6H-Pyrrolo[2,3- H.1.16 1.83 (a) 459pyrrolo[2,3-e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan- a]pyrazin-1- 1-yl)benzenesulfonamide(prepared yl)bicyclo[2.2.2]octan-1- using A from Preparation #9, 4-yl)-3,4- (tert- difluorobenzenesulfonamidebutoxycarbonylamino)bicyclo[2.2.2]octane- 1-carboxylic acid [PrimeOrganics], HATU, and TEA, C with TEA, I with 4N HCl in 1,4-dioxane, Nwith 3,4-difluorobenzene-1- sulfonyl chloride [Maybridge] and TEA)N-(4-(6-Tosyl-6H-pyrrolo[2,3- N-(4-(6H-Pyrrolo[2,3- H.1.17 1.78 (a) 465e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)bicyclo[2.2.2]octan-1- a]pyrazin-1- yl)benzo[c][1,2,5]oxadiazole-4-yl)bicyclo[2.2.2]octan-1- sulfonamide (prepared using A fromyl)benzo[c][1,2,5]oxadiazole- Preparation #9, 4-(tert- 4-sulfonamidebutoxycarbonylamino)bicyclo[2.2.2]octane- 1-carboxylic acid [PrimeOrganics], HATU, and TEA, C with TEA, I with 4N HCl in 1,4-dioxane, Nwith benzo[c][1,2,5]oxadiazole-4- sulfonyl chloride [Maybridge] and TEA)N-Methyl-N-(4-(6-tosyl-6H- N-(4-(6H-Pyrrolo[2,3- H.1.18 1.70 (a) 401pyrrolo[2,3-e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan- a]pyrazin-1-1-yl)cyclopropanesulfonamide yl)bicyclo[2.2.2]octan-1- (prepared using Afrom Preparation yl)-N- #9, 4-(tert- methylcyclopropanesulfonamidebutoxycarbonylamino)bicyclo[2.2.2]octane- 1-carboxylic acid [PrimeOrganics], HATU, and TEA, C with TEA, I with 4N HCl in 1,4-dioxane, Nwith cyclopropanesulfonyl chloride [Matrix] and TEA, Z with methyliodide) N-(3-Ethyl-4-(6-tosyl-6H- N-((1S,3R,4S)-3-Ethyl-4- H.1.19 1.75(a) 389 pyrrolo[2,3-e][1,2,4]triazolo[4,3- (6H-pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)cyclobutanesulfonamidea]pyrazin-1- (prepared using N fromyl)cyclopentyl)cyclobutanesulfonamide Preparation #FF.1 and and N-cyclobutanesulfonyl chloride ((1R,3S,4R)-3-Ethyl-4-(6H- [Hande], GG withNaOH, A with pyrrolo[2,3- Preparation #9, HATU, and TEA, Ce][1,2,4]triazolo[4,3- with TEA) a]pyrazin-1-yl)cyclopentyl)cyclobutanesulfonamide (1:1) N-3-Ethyl-4-(6-tosyl-6H-N-((1S,3R,4S)-3-Ethyl-4- H.1.20 1.82 (a) 403pyrrolo[2,3-e][1,2,4]triazolo[4,3- (6H-pyrrolo[2,3-e][1,2,4]triazolo-a]pyrazin-1- [4,3-a]pyrazin-1- yl)cyclopentyl)cyclopentanesulfonamideyl)cyclopentyl)cyclopentanesulfonamide (prepared using N from and N-Preparation #FF.1 and ((1R,3S,4R)-3-ethyl-4-(6H- cyclopentanesulfonylchloride, GG pyrrolo[2,3-e][1,2,4]triazolo with NaOH, A with Preparation#9, [4,3-a]pyrazin-1-yl) HATU, and TEA, C with TEA)cyclopentyl)cyclopentanesulfonamide (1:1) 6-(-3-Ethyl-4-(6-tosyl-6H-6-((1S,3R,4S)-3-Ethyl-4- H.1.21 1.85 (a) 373pyrrolo[2,3-e][1,2,4]triazolo[4,3- (6H-pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentylamino)nicotinonitrile a]pyrazin-1-(prepared using P from Preparation yl)cyclopentylamino)nicotinonitrile#FF.1 and di-tert-butyl dicarbonate, and 6-((1R,3S,4R)- GG with NaOH, Awith Preparation 3-ethyl-4-(6H-pyrrolo[2,3- #9, HATU, and TEA, C withTEA, e][1,2,4]triazolo[4,3- I with 4N HCl in 1,4-dioxane, O a]pyrazin-1-with 6-fluoronicotinonitrile yl)cyclopentylamino)nicotinonitrile[Matrix]) (1:1) N-(3-Ethyl-4-(6-tosyl-6H- N-((1S,3R,4R)-3-Ethyl-4-H.1.22 1.75 (a) 389 pyrrolo[2,3-e][1,2,4]triazolo[4,3- (6H-pyrrolo[2,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)cyclobutanesulfonamide a]pyrazin-1- (prepared using Nfrom yl)cyclopentyl)cyclobutanesulfonamide Preparation #FF.1 and and N-cyclobutanesulfonyl chloride ((1R,3S,4S)-3-ethyl-4-(6H- [Hande], GG withNaOH, A with pyrrolo[2,3- Preparation #9, HATU, and TEA, Ce][1,2,4]triazolo[4,3- with TEA) a]pyrazin-1-yl)cyclopentyl)cyclobutanesulfonamide (1:1) 6-(-3-Ethyl-4-(6-tosyl-6H-6-((1S,3R,4R)-3-Ethyl-4- H.1.23 1.79 (a) 373pyrrolo[2,3-e][1,2,4]triazolo[4,3- (6H-pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentylamino)nicotinonitrile a]pyrazin-1-(prepared using P from Preparation yl)cyclopentylamino)nicotinonitrile#FF.1 and di-tert-butyl dicarbonate, and 6-((1R,3S,4S)- GG with NaOH, Awith Preparation 3-ethyl-4-(6H-pyrrolo[2,3- #9, HATU, and TEA, C withTEA, e][1,2,4]triazolo[4,3- I with 4N HCl in 1,4-dioxane, O a]pyrazin-1-with 6-fluoronicotinonitrile yl)cyclopentylamino)nicotinonitrile[Matrix]) (1:1) 5-Chloro-6-((1S,3R)-3-(6-tosyl-6H- 6-((1S,3R)-3-(6H-H.1.24 1.96 (a) 379 pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3-a]pyrazin-1- e][1,2,4]triazolo[4,3- yl)cyclopentylamino)nicotinonitrilea]pyrazin-1- (prepared using C from Preparation yl)cyclopentylamino)-5-#A.1 with TEA, I with 4 N HCl in chloronicotinonitrile 1,4-dioxane, Owith 5,6- dichloronicotinonitrile) 6-((1S,3R)-3-(6-Tosyl-6H-6-((1S,3R)-3-(6H- H.1.25 2.05 (a) 413 pyrrolo[2,3-e][1,2,4]triazolo[4,3-Pyrrolo[2,3- a]pyrazin-1-yl)cyclopentylamino)- e][1,2,4]triazolo[4,3-4-(trifluoromethyl)nicotinonitrile a]pyrazin-1- (prepared using C fromPreparation yl)cyclopentylamino)-4- #A.1, I with 4 N HCl in 1,4-(trifluoromethyl)nicotinonitrile dioxane, O with Preparation #HH.1)N-((1S,2R,4S,5R)-5-Methyl-4-(6H- N-((1S,2R,4S,5R)-5-Methyl- H.1.26 1.51(a) 373 pyrrolo[2,3-e][1,2,4]triazolo[4,3- 4-(6H-pyrrolo[2,3-a]pyrazin-1-yl)bicyclo[3.1.0]hexan- e][1,2,4]triazolo[4,3-2-yl)cyclopropanesulfonamide a]pyrazin-1- benzenesulfonamide and N-yl)bicyclo[3.1.0]hexan-2- ((1R,2S,4R,5S)-5-methyl-4-(6H-yl)cyclopropanesulfonamide pyrrolo[2,3-e][1,2,4]triazolo[4,3- andN-((1R,2S,4R,5S)-5- a]pyrazin-1-yl)bicyclo[3.1.0]hexan-methyl-4-(6H-pyrrolo[2,3- 2-yl)cyclopropanesulfonamidee][1,2,4]triazolo[4,3- benzenesulfonamide (prepared a]pyrazin-1- using Afrom Preparation #9 and yl)bicyclo[3.1.0]hexan-2- Preparation #11, HATU,and TEA, yl)cyclopropanesulfonamide C with TEA)N-((1S,3S,4R)-4-Ethyl-3-methyl-3- N-((1S,3S,4R)-4-Ethyl-3- H.1.27 1.74(a) 387 (6-tosyl-6H-pyrrolo[2,3- methyl-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)cyclopropanesulfonamide a]pyrazin-1- andN-((1R,3R,4S)-4-ethyl-3- yl)cyclopentyl)cyclopropanesulfonamidemethyl-3-(6-tosyl-6H-pyrrolo[2,3- and N-e][1,2,4]triazolo[4,3-a]pyrazin-1- ((1R,3R,4S)-4-ethyl-3-yl)cyclopentyl)cyclopropanesulfonamide methyl-3-(6H-pyrrolo[2,3-benzenesulfonamide (prepared e][1,2,4]triazolo[4,3- using A fromPreparation #9 and a]pyrazin-1- Preparation #13, HATU, and TEA,yl)cyclopentyl)cyclopropanesulfonamide C with TEA)4-Methoxy-N-((1S,3R)-3-(6-tosyl- N-((1S,3R)-3-(6H- H.1.28 1.75 (a) 4136H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using A from Preparation yl)cyclopentyl)-4- #9,(1R,3S)-3-(tert- methoxybenzenesulfonamidebutoxycarbonylamino)cyclopentane carboxylic acid [Chem-Impex], EDC-HCl,C with TEA, I with 4N HCl in 1,4-dioxane, N with 4-methoxybenzene-1-sulfonyl chloride and DIEA)4-Methyl-N-((1S,3R)-3-(6-tosyl-6H- N-((1S,3R)-3-(6H- H.1.29 1.82 (a) 397pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using A from Preparation yl)cyclopentyl)-4- #9,(1R,3S)-3-(tert- methylbenzenesulfonamidebutoxycarbonylamino)cyclopentane carboxylic acid [Chem-Impex], EDC-HCl,C with TEA, I with 4N HCl in 1,4-dioxane, N with 4-methylbenzene-1-sulfonyl chloride and DIEA)2-Chloro-N-((1S,3R)-3-(6-tosyl-6H- N-((1S,3R)-3-(6H- H.1.30 1.82 (a) 417pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using A from Preparation yl)cyclopentyl)-2- #9,(1R,3S)-3-(tert- chlorobenzenesulfonamidebutoxycarbonylamino)cyclopentane carboxylic acid [Chem-Impex], EDC•HCl,C with TEA, I with 4N HCl in 1,4-dioxane, N with 2-chlorobenzene-1-sulfonyl chloride [Lancaster] and DIEA)2,3-Dichloro-N-((1S,3R)-3-(6-tosyl- N-((1S,3R)-3-(6H- H.1.31 1.93 (a)450 6H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using A from Preparation yl)cyclopentyl)-2,3- #9,(1R,3S)-3-(tert- dichlorobenzenesulfonamidebutoxycarbonylamino)cyclopentane carboxylic acid [Chem-Impex], andEDC•HCl, C with TEA, I with 4N HCl in 1,4-dioxane, N with 2,3-dichlorobenzene-1-sulfonyl chloride [Lancaster] and DIEA)1-Cyano-N-(((1S,3R)-3-(6-tosyl-(6H- N-(((1S,3R)-3-6H- H.1.32 1.57 (a)350 pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)methyl)cyclopropanecarboxamidea]pyrazin-1- (prepared using A yl)cyclopentyl)methyl)-1- fromPreparation #9, Preparation cyanocyclopropanecarboxamide #P.1, andEDC•HCl, C with TEA, I with 4N HCl in 1,4-dioxane, L with1-cyanocyclopropanecarboxylic acid and DIEA)3-Cyano-4-fluoro-N-((1S,3R)-3-(6- N-((1S,3R)-3-(6H- H.1.33 1.84 (a) 426tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using A from Preparation yl)cyclopentyl)-3-cyano-4- #9,(1R,3S)-3-(tert- fluorobenzenesulfonamidebutoxycarbonylamino)cyclopentane carboxylic acid [Chem-Impex], EDC•HCl,C with TEA, I with 4N HCl in 1,4-dioxane, N with 3-cyano-4-fluorobenzene-1-sulfonyl chloride and DIEA)3,4-Difluoro-N-((1S,3R)-3-(6-tosyl- N-((1S,3R)-3-(6H- H.1.34 1.86 (a)419 6H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using A from Preparation yl)cyclopentyl)-3,4- #9,(1R,3S)-3-(tert- difluorobenzenesulfonamidebutoxycarbonylamino)cyclopentane carboxylic acid [Chem-Impex], EDC•HCl,C with TEA, I with 4N HCl in 1,4-dioxane, N with 3,4-difluorobenzene-1-sulfonyl chloride [Maybridge] and DIEA)5-(-3-Ethyl-4-(6-tosyl-6H- 5-((1S,3R,4R)-3-Ethyl-4- H.1.35 1.76 (a) 374pyrrolo[2,3-e][1,2,4]triazolo[4,3- (6H-pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentylamino)pyrazine-2- a]pyrazin-1-carbonitrile (prepared using O from yl)cyclopentylamino)pyrazine-Example #18, Step M and 5- 2-carbonitrile and 5-chloropyrazine-2-carbonitrile [Ark ((1R,3S,4S)-3-ethyl-4-(6H- Pharm])pyrrolo[2,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)cyclopentylamino)pyrazine- 2-carbonitrileN-Methyl-N-((1S,3R)-3-(6-tosyl- N-((1S,3R)-3-(6H- H.1.36 1.64 (a) 3616H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)cyclopropanesulfonamidea]pyrazin-1- (prepared using A from yl)cyclopentyl)-N- Preparation #9,4-(tert- methylcyclopropanesulfonamidebutoxycarbonylamino)bicyclo[2.2.2]octane- 1-carboxylic acid [PrimeOrganics], HATU, and TEA, C with TEA, I with 4N HCl in 1,4-dioxane, andN with cyclopropanesulfonyl chloride [Matrix] and TEA, Z with methyliodide) N-(4-(6-Tosyl-6H-pyrrolo[2,3- N-(4-(6H-Pyrrolo[2,3- H.1.37 1.56(a) 373 e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)bicyclo[2.2.1]heptan-1- a]pyrazin-1- yl)cyclopropanesulfonamideyl)bicyclo[2.2.1]heptan-1- (prepared using A from Preparationyl)cyclopropanesulfonamide #9, Preparation #26, and HATU, C with TEA, Iwith 4N HCl in 1,4- dioxane, N with cyclopropanesulfonyl chloride[Matrix] and TEA) 6-(4-(6-Tosyl-6H-pyrrolo[2,3- 6-(4-(6H-Pyrrolo[2,3-H.1.38 1.86 (a) 371 e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)bicyclo[2.2.1]heptan-1- a]pyrazin-1-ylamino)nicotinonitrile (prepared yl)bicyclo[2.2.1]heptan-1- using Afrom Preparation #9, ylamino)nicotinonitrile Preparation #26, and HATU,C with TEA, I with 4N HCl in 1,4-dioxane, O with 6-fluoronicotinonitrile[Matrix] and DIEA) N-(4-(6-Tosyl-6H-pyrrolo[2,3- N-(4-(6H-Pyrrolo[2,3-H.1.39 1.82 (a) 400 e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)bicyclo[2.2.2]octan-1- a]pyrazin-1-yl)benzo[d]oxazol-2-amine yl)bicyclo[2.2.2]octan-1- (prepared using O.1from Example yl)benzo[d]oxazol-2-amine #7, Step B and 2-chlorobenzo[d]oxazole [TCI]) N-((1R,2R,4S,5S)-4-(6-Tosyl-6H-N-((1R,2R,4S,5S)-4-(6H- H.1.40 1.72 (a) 359pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3-a]pyrazin-1-yl)bicyclo[3.1.0]hexan- e][1,2,4]triazolo[4,3-2-yl)cyclopropanesulfonamide a]pyrazin-1- (prepared using N fromPreparation yl)bicyclo[3.1.0]hexan-2- #15 with cyclopropylsulfonylyl)cyclopropanesulfonamide chloride and TEA)N-((1S,2R,4S,5R)-4-(6-Tosyl-6H- N-((1S,2R,4S,5R)-4-(6H- H.1.41 1.58 (a)359 pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3-a]pyrazin-1-yl)bicyclo[3.1.0]hexan- e][1,2,4]triazolo[4,3-2-yl)cyclopropanesulfonamide a]pyrazin-1- (prepared using N fromPreparation yl)bicyclo[3.1.0]hexan-2- #18 with cyclopropylsulfonylyl)cyclopropanesulfonamide chloride and TEA)3,4-Dichloro-N-((1S,3R)-3-(6-tosyl- N-((1S,3R)-3-(6H- H.1.42 2.00 (a)451 6H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using C from Example yl)cyclopentyl)-3,4- #6, Step A with TEA,I with 4 N dichlorobenzenesulfonamide HCl in 1,4-dioxane, N from 3,4-dichlorobenzene-1-sulfonyl chloride) 3,5-Dichloro-N-((1S,3R)-3-(6-tosyl-N-((1S,3R)-3-(6H- H.1.43 2.03 (a) 451 6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)benzenesulfonamide a]pyrazin-1- (prepared using C fromExample yl)cyclopentyl)-3,5- #6, Step A with TEA, I with 4 Ndichlorobenzenesulfonamide HCl in 1,4-dioxane, N from 3,5-dichlorobenzene-1-sulfonyl chloride) N-((1S,3R)-3-(6-Tosyl-6H-N-((1S,3R)-3-(6H- H.1.44 1.75 (a) 390 pyrrolo[2,3-e][1,2,4]triazolo[4,3-Pyrrolo[2,3- a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)piperidine-1- a]pyrazin-1- sulfonamide (prepared using Cfrom yl)cyclopentyl)piperidine-1- Example #6, Step A with TEA, Isulfonamide with 4 N HCl in 1,4-dioxane, N from piperidine-1-sulfonylchloride) N-((1S,3R)-3-(6-Tosyl-6H- N-((1S,3R)-3-(6H- H.1.45 1.53 (a)392 pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)morpholine-4- a]pyrazin-1-sulfonamide (prepared using C from yl)cyclopentyl)morpholine- Example#6, Step A with TEA, I 4-sulfonamide with 4 N HCl in 1,4-dioxane, N frommorpholine-4-sulfonyl chloride) 6-((1R,3S)-3-(6-Tosyl-6H-6-((1R,3S)-3-(6H- H.1.46 1.82 (a) 344 imidazo[1,5-a]pyrrolo[2,3-Imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1- e]pyrazin-1-yl)cyclopentylamino)nicotinonitrile yl)cyclopentylamino)nicotinonitrile(prepared using C from Example #6, Step A with TEA, I with 4 N HCl in1,4-dioxane, O from 5- cyano-2-fluoropyridine [Matrix])N-(cis-3-Methyl-4-(6-tosyl-6H- N-(cis-3-Methyl-4-(6H- H.1.47 1.75 (a)389 pyrrolo[2,3-e][1,2,4]triazolo[4,3- pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)cyclopentanesulfonamidea]pyrazin-1- (prepared using GG fromyl)cyclopentyl)cyclopentanesulfonamide Example #14, Step E, P, A fromPreparation #9, and HATU, C with TEA, N with cyclopentanesulfonylchloride [Matrix] and DIEA) 5-(cis-3-Methyl-4-(6-tosyl-6H-5-(cis-3-Methyl-4-(6H- H.1.48 1.73 (a) 359pyrrolo[2,3-e][1,2,4]triazolo[4,3- pyrrolo[2,3-a]pyrazin-1-yl)cyclopentylamino)picolinonitrile e][1,2,4]triazolo[4,3-(prepared using GG a]pyrazin-1- from Example #14, Step E, P, Ayl)cyclopentylamino)picolinonitrile from Preparation #9, and HATU, Cwith TEA, O with 5- fluoropicolinonitrile and DIEA)N-(cis-3-Methyl-4-(6-tosyl-6H- N-(cis-3-Methyl-4-(6H- H.1.49 1.67 (a)375 pyrrolo[2,3-e][1,2,4]triazolo[4,3- pyrrolo[2,3-a]pyrazin-1-yl)cyclopentyl)cyclobutanesulfonamide e][1,2,4]triazolo[4,3-(prepared using GG from Example a]pyrazin-1- #14, Step E, P, A fromPreparation yl)cyclopentyl)cyclobutanesulfonamide #9, and HATU, C withTEA, N with cyclobutanesulfonyl chloride [Hande] and DIEA)5-(cis-3-Methyl-4-(6-tosyl-6H- 5-(cis-3-Methyl-4-(6H- H.1.50 1.74 (a)360 pyrrolo[2,3-e][1,2,4]triazolo[4,3- pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentylamino)pyrazine-2- a]pyrazin-1-carbonitrile yl)cyclopentylamino)pyrazine- (prepared using GG fromExample 2-carbonitrile #14, Step E, P, A from Preparation #9, and HATU,C with TEA, O with 5-chloropyrazine-2-carbonitrile and DIEA)N-(3a-(6-Tosyl-6H-pyrrolo[2,3- N-(3a-(6H-Pyrrolo[2,3- H.1.51 1.60 (a)387 e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)octahydropentalen-2- a]pyrazin-1- yl)cyclopropanesulfonamideyl)octahydropentalen-2- (prepared using EE from ethyl 2-yl)cyclopropanesulfonamide oxooctahydropentalene-3a- carboxylate(Tetrahedron Letters (1995), 36(41), 7375-8), FF, K with aceticanhydride, GG, A from Preparation #9, and HATU, C with TEA, JJ with 6 NHCl, N with cyclopropanesulfonyl chloride [Matrix] and DIEA)N-((1S,3R,4S)-3-Methyl-4-(6-tosyl- N-((1S,3R,4S)-3-Methyl-4- H.1.52 1.65(a) 361 6H-pyrrolo[2,3- (6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)cyclopropanesulfonamide a]pyrazin-1- andN-((1R,3S,4R)-3-methyl- yl)cyclopentyl)cyclopropanesulfonamide4-(6-tosyl-6H-pyrrolo[2,3- and N- e][1,2,4]triazolo[4,3-a]pyrazin-1-((1R,3S,4R)-3-methyl-4- yl)cyclopentyl)cyclopropanesulfonamide(6H-pyrrolo[2,3- (1:1) (prepared using GG e][1,2,4]triazolo[4,3- fromExample #14, Step F with a]pyrazin-1- LiOH, A with Preparation #9,yl)cyclopentyl)cyclopropanesulfonamide HATU and TEA, C with TEA) (1:1)N-3,3-Dimethyl-4-(6-tosyl-6H- N-((1R,4S)-3,3-Dimethyl-4- H.1.53 1.76 (a)375 pyrrolo[2,3-e][1,2,4]triazolo[4,3- (6H-pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)cyclopropanesulfonamidea]pyrazin-1- (prepared using EE fromyl)cyclopentyl)cyclopropanesulfonamide Preparation #25 with N,N- and N-dibenzylamine, Y with EtOH, FF, ((1S,4R)-3,3-dimethyl-4- N withcyclopropylsulfonyl (6H-pyrrolo[2,3- chloride, GG with LiOH, A withe][1,2,4]triazolo[4,3- Preparation #9, HATU, and TEA, C a]pyrazin-1-with TEA) yl)cyclopentyl)cyclopropanesulfonamide (1:1)N-3,3-Dimethyl-4-(6-tosyl-6H- N-((1R,4R)-3,3-Dimethyl-4- H.1.54 1.65 (a)375 pyrrolo[2,3-e][1,2,4]triazolo[4,3- (6H-pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)cyclopropanesulfonamidea]pyrazin-1- (prepared using EE fromyl)cyclopentyl)cyclopropanesulfonamide Preparation #25 with N,N- and N-dibenzylamine, Y with EtOH, FF, ((1S,4S)-3,3-dimethyl-4- N withcyclopropylsulfonyl (6H-pyrrolo[2,3- chloride, GG with LiOH, A withe][1,2,4]triazolo[4,3- Preparation #9, HATU, and TEA, C a]pyrazin-1-with TEA) yl)cyclopentyl)cyclopropanesulfonamide (1:1)N-((1S,3R,4S)-3-Ethyl-4-(6-tosyl- N-((1S,3R,4S)-3-Ethyl-4- H.1.55 1.75(a) 375 6H-pyrrolo[2,3- (6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)cyclopropanesulfonamide a]pyrazin-1- andN-((1R,3S,4R)-3-ethyl-4- yl)cyclopentyl)cyclopropanesulfonamide(6-tosyl-6H-pyrrolo[2,3- and N- e][1,2,4]triazolo[4,3-a]pyrazin-1-((1R,3S,4R)-3-ethyl-4-(6H- yl)cyclopentyl)cyclopropanesulfonamidepyrrolo[2,3- (1:1) (prepared using GG e][1,2,4]triazolo[4,3- fromExample #15, Step F with a]pyrazin-1- LiOH, A with Preparation #9,yl)cyclopentyl)cyclopropanesulfonamide HATU, and TEA, C with TEA) (1:1)N-((1S,3R,4S)-3-Methyl-4-(6-tosyl- N-((1S,3S,4R)-3-(6H- H.1.56 1.83 (a)360 6H-imidazo[1,5-a]pyrrolo[2,3- Imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1- e]pyrazin-1-yl)-4- yl)cyclopentyl)cyclopropanesulfonamidemethylcyclopentyl)cyclopropanesulfonamide and N-((1R,3S,4R)-3-methyl-and N- 4-(6-tosyl-6H-imidazo[1,5- ((1R,3R,4S)-3-(6H-a]pyrrolo[2,3-e]pyrazin-1- imidazo[1,5-a]pyrrolo[2,3-yl)cyclopentyl)cyclopropanesulfonamide e]pyrazin-1-yl)-4- (1:1)(prepared using GG methylcyclopentyl)cyclopropanesulfonamide fromExample #14, Step F with (1:1) LiOH, L with Example #13, Step F, HATU,and TEA, C with TEA) N-((1S,3R,4S)-3-Ethyl-4-(6-tosyl-N-((1S,3S,4R)-3-6H- H.1.57 1.93 (a) 374 6H-imidazo[1,5-a]pyrrolo[2,3-Imidazo[1,5-a]pyrrolo[2,3- e]pyrazin-1- e]pyrazin-1-yl)-4-yl)cyclopentyl)cyclopropanesulfonamideethylcyclopentyl)cyclopropanesulfonamide and N-((1R,3S,4R)-3-ethyl-4-and N- (6-tosyl-6H-imidazo[1,5- ((1R,3R,4S)-3-(6H-a]pyrrolo[2,3-e]pyrazin-1- imidazo[1,5-a]pyrrolo[2,3-yl)cyclopentyl)cyclopropanesulfonamide e]pyrazin-1-yl)-4- (1:1)(prepared using GG ethylcyclopentyl)cyclopropanesulfonamide from Example#15, Step F with (1:1) LiOH, L with Example #13, Step F, HATU, and TEA,AA with Belleau's reagent) N-3-Isopropyl-4-(6-tosyl-6H-N-((1S,3S,4R)-3-Isopropyl- H.1.58 1.79 (a) 389pyrrolo[2,3-e][1,2,4]triazolo[4,3- 4-(6H-pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)cyclopropanesulfonamidea]pyrazin-1- (prepared using BB from ethylyl)cyclopentyl)cyclopropanesulfonamide 4-methyl-3-oxopentanoate with andN- methyl 4-chloro-3-oxobutanoate, ((1R,3R,4S)-3-isopropyl-4- CC withsodium iodide, DD, EE (6H-pyrrolo[2,3- with N,N-dibenzylamine, FF, Ne][1,2,4]triazolo[4,3- with cyclopropylsulfonyl chloride, a]pyrazin-1-GG with LiOH, A with Preparation yl)cyclopentyl)cyclopropanesulfonamide#9, HATU, and TEA, C with TEA) (1:1) N-3-Isopropyl-4-(6-tosyl-6H-N-((1S,3R,4S)-3-Isopropyl- H.1.59 1.87 (a) 389pyrrolo[2,3-e][1,2,4]triazolo[4,3- 4-(6H-pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)cyclopropanesulfonamidea]pyrazin-1- (prepared using BB from ethylyl)cyclopentyl)cyclopropanesulfonamide 4-methyl-3-oxopentanoate with andN- methyl 4-chloro-3-oxobutanoate, ((1R,3S,4R)-3-isopropyl-4- CC withsodium iodide, DD, EE (6H-pyrrolo[2,3- with N,N-dibenzylamine, FF, Ne][1,2,4]triazolo[4,3- with cyclopropylsulfonyl chloride, a]pyrazin-1-GG with LiOH, A with Preparation yl)cyclopentyl)cyclopropanesulfonamide#9, HATU, and TEA, C with TEA) (1:1) N-3-Isopropyl-4-(6-tosyl-6H-N-((1S,3S,4S)-3-Isopropyl- H.1.60 1.90 (a) 389pyrrolo[2,3-e][1,2,4]triazolo[4,3- 4-(6H-pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)cyclopropanesulfonamidea]pyrazin-1- (prepared using BB from ethylyl)cyclopentyl)cyclopropanesulfonamide 4-methyl-3-oxopentanoate with andN- methyl 4-chloro-3-oxobutanoate, ((1R,3R,4R)-3-isopropyl-4- CC withsodium iodide, DD, EE (6H-pyrrolo[2,3- with N,N-dibenzylamine, FF, Ne][1,2,4]triazolo[4,3- with cyclopropylsulfonyl chloride, a]pyrazin-1-GG with LiOH, A with Preparation yl)cyclopentyl)cyclopropanesulfonamide#9, HATU, and TEA, C with TEA) N-((1S,3R,4S)-3-Ethyl-4-(3-methyl-N-((1S,3R,4S)-3-Ethyl-4-(3- H.1.61 1.93 (a) 388 6-tosyl-6H-imidazo[1,5-methyl-6H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1-a]pyrrolo[2,3-e]pyrazin-1- yl)cyclopentyl)cyclopropanesulfonamideyl)cyclopentyl)cyclopropanesulfonamide and N-((1R,3S,4R)-3-ethyl-4- andN- (3-methyl-6-tosyl-6H-imidazo[1,5- ((1R,3S,4R)-3-ethyl-4-(3-a]pyrrolo[2,3-e]pyrazin-1- methyl-6H-imidazo[1,5-yl)cyclopentyl)cyclopropanesulfonamide a]pyrrolo[2,3-e]pyrazin-1- (1:1)(prepared using N from yl)cyclopentyl)cyclopropanesulfonamidePreparation #FF.1 and (1:1) cyclopropylsulfonyl chloride with TEA, GGwith LiOH, L with Preparation #24, HATU, and TEA, AA with Lawesson'sreagent) Cyclopropanesulfonic acid Cyclopropanesulfonic acid H.1.62 1.70(a) 413 {(3R,7S)-5-[6-(tosyl)-6H- [(3R,7S)-5-(6H-pyrrolo[2,3-pyrrolo[2,3-e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl]-adamantan-2-yl}- a]pyrazin-1-yl)-adamantan- amide(prepared using A from 2-yl]-amide Preparation #9 and Preparation #22, Cwith DIEA, JJ, N with cyclopropylsulfonyl chloride [Matrix], and DIEA4-Cyano-N-((1R,3S)-2,2-dimethyl- 4-(N-((1R,3S)-2,2- H.1.63 1.57 (a) 4403-(6-tosyl-6H-pyrrolo[2,3- Dimethyl-3-(6H-e][1,2,4]triazolo[4,3-a]pyrazin-1- pyrrolo[2,3-yl)cyclobutyl)benzenesulfonamide e][1,2,4]triazolo[4,3- (prepared usingA from (1S,3R)-3- a]pyrazin-1- acetamido-2,2-yl)cyclobutyl)sulfamoyl)benzamide dimethylcyclobutanecarboxylic acid[prepared as described in Tetrahedron: Asymmetry 2008, 19, 302-308] andPreparation #9 with EDC, C with DIEA, JJ, N with 4-cyanobenzene-1-sulfonyl chloride [Maybridge] and DIEA)5-Cyano-N-((1R,3S)-2,2-dimethyl- 6-(N-((1R,3S)-2,2- H.1.64 1.45 (a) 4413-(6-tosyl-6H-pyrrolo[2,3- Dimethyl-3-(6H-e][1,2,4]triazolo[4,3-a]pyrazin-1- pyrrolo[2,3-yl)cyclobutyl)pyridine-2- e][1,2,4]triazolo[4,3- sulfonamide(Preparation #21) a]pyrazin-1- yl)cyclobutyl)sulfamoyl)nicotinamide5-Cyano-N-((1R,3S)-2,2-dimethyl- 5-Cyano-N-((1R,3S)-2,2- H.1.65 1.81 (a)423 3-(6-tosyl-6H-pyrrolo[2,3- dimethyl-3-(6H-e][1,2,4]triazolo[4,3-a]pyrazin-1- pyrrolo[2,3-yl)cyclobutyl)pyridine-2- e][1,2,4]triazolo[4,3- sulfonamide(Preparation #21) a]pyrazin-1- yl)cyclobutyl)pyridine-2- sulfonamide2-Cyano-N-((1S,3R)-3-(6-tosyl-6H- N-((1S,3R)-3-(6H- H.1.66 1.24 (d) 408pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3-a]pyrazin-1-yl)cyclopentyl)benzenesulfonamide e][1,2,4]triazolo[4,3-(prepared a]pyrazin-1- using I from Preparation #C.1, Nyl)cyclopentyl)-2- with 2-cyanobenzenesulfonyl cyanobenzenesulfonamidechloride and DIEA) 3-(Difluoromethoxy)-N-((1S,3R)-3- N-((1S,3R)-3-(6H-H.1.67 1.32 (d) 449 (6-tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)benzenesulfonamide a]pyrazin-1- (prepared using I fromPreparation yl)cyclopentyl)-3- #C.1, N with 3-(difluoromethoxy)benzenesulfonamide (difluoromethoxy)benzenesulfonylchloride and DIEA) 3,4,5-Trifluoro-N-((1S,3R)-3-(6- N-((1S,3R)-3-(6H-H.1.68 1.34 (d) 437 tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)benzenesulfonamide a]pyrazin-1- (prepared using I fromPreparation yl)cyclopentyl)-3,4,5- #C.1, N with 3,4,5-trifluorobenzenesulfonamide trifluorobenzenesulfonyl chloride and DIEA)5-Chloro-N-((1S,3R)-3-(6-tosyl-6H- N-((1S,3R)-3-(6H- H.1.69 1.33 (d) 423pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)thiophene-2- a]pyrazin-1-sulfonamide (prepared using I from yl)cyclopentyl)-5- Preparation #C.1,N with 5- chlorothiophene-2- chlorothiophene-2-sulfonyl chloridesulfonamide and DIEA) 5-(Dimethylamino)-N-((1S,3R)-3- N-((1S,3R)-3-(6H-H.1.70 1.36 (d) 476 (6-tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)naphthalene-1- a]pyrazin-1- sulfonamide (prepared using Ifrom yl)cyclopentyl)-5- Preparation #C.1, N with dansyl(dimethylamino)naphthalene- chloride and DIEA) 1-sulfonamide2,2,4,6,7-Pentamethyl-N-((1S,3R)- N-((1S,3R)-3-(6H- H.1.71 1.41 (d) 4953-(6-tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)-2,3- a]pyrazin-1- dihydrobenzofuran-5-sulfonamideyl)cyclopentyl)-2,2,4,6,7- (prepared using I from Preparationpentamethyl-2,3- #C.1, N with 2,2,4,6,7-pentamethyl-dihydrobenzofuran-5- 2,3-dihydrobenzofuran-5-sulfonyl sulfonamidechloride and DIEA) 4-(Difluoromethoxy)-N-((1S,3R)-3- N-((1S,3R)-3-(6H-H.1.72 1.32 (d) 449 (6-tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)benzenesulfonamide a]pyrazin-1- (prepared using I fromPreparation yl)cyclopentyl)-4- #C.1, N with 4-(difluoromethoxy)benzenesulfonamide (difluoromethoxy)benzenesulfonylchloride and DIEA) 4-Bromo-3-fluoro-N-((1S,3R)-3-(6- N-((1S,3R)-3-(6H-H.1.73 1.33 (d) 479 tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)benzenesulfonamide a]pyrazin-1- (prepared using I fromPreparation yl)cyclopentyl)-4-bromo-3- #C.1, N with 4-bromo-3-fluorobenzenesulfonamide fluorobenzenesulfonyl chloride and DIEA)3-Chloro-2-fluoro-N-((1S,3R)-3-(6- N-((1S,3R)-3-(6H- H.1.74 1.31 (d) 435tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-3-chloro-2- #C.1, Nwith 3-chloro-2- fluorobenzenesulfonamide fluorobenzenesulfonyl chlorideand DIEA) 3-Methoxy-N-((1S,3R)-3-(6-tosyl- N-((1S,3R)-3-(6H- H.1.75 1.29(d) 413 6H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamidea]pyrazin-1-yl)cyclopentyl)- (prepared using I from Preparation 3- #C.1,N with 3- methoxybenzenesulfonamide methoxybenzenesulfonyl chloride andDIEA) 4-Acetyl-N-((1S,3R)-3-(6-tosyl-6H- N-((1S,3R)-3-(6H- H.1.76 1.26(d) 425 pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-4- #C.1, N with 4-acetylbenzenesulfonamide acetylbenzenesulfonyl chloride and DIEA)3-Methyl-N-((1S,3R)-3-(6-tosyl-6H- N-((1S,3R)-3-(6H- H.1.77 1.30 (d) 397pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-3- #C.1, N withm-toluenesulfonyl methylbenzenesulfonamide chloride and DIEA)3,5-Difluoro-N-((1S,3R)-3-(6-tosyl- N-((1S,3R)-3-(6H- H.1.78 1.31 (d)419 6H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-3,5- #C.1, N with3,5- difluorobenzenesulfonamide difluorobenzenesulfonyl chloride andDIEA) 3-Chloro-2-methyl-N-((1S,3R)-3-(6- N-((1S,3R)-3-(6H- H.1.79 1.35(d) 431 tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)benzenesulfonamide a]pyrazin-1- (prepared using I fromPreparation yl)cyclopentyl)-3-chloro-2- #C.1, N with 3-chloro-2-methylbenzenesulfonamide methylbenzenesulfonyl chloride and DIEA)3,5-Dimethyl-N-((1S,3R)-3-(6-tosyl- N-((1S,3R)-3-(6H- H.1.80 1.31 (d)411 6H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-3,5- #C.1, N with3,5- dimethylbenzenesulfonamide dimethylbenzenesulfonyl chloride andDIEA) 3-Fluoro-N-((1S,3R)-3-(6-tosyl-6H- N-((1S,3R)-3-(6H- H.1.81 1.29(d) 401 pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-3- #C.1, N with 3-fluorobenzenesulfonamide fluorobenzenesulfonyl chloride and DIEA)3-Chloro-4-methyl-N-((1S,3R)-3-(6- N-((1S,3R)-3-(6H- H.1.82 1.34 (d) 431tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-3-chloro-4- #C.1, Nwith 3-chloro-4- methylbenzenesulfonamide methylbenzenesulfonyl chlorideand DIEA) 2,4-Dichloro-N-((1S,3R)-3-(6-tosyl- N-((1S,3R)-3-(6H- H.1.831.35 (d) 451 6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)benzenesulfonamide a]pyrazin-1- (prepared using I fromPreparation yl)cyclopentyl)-2,4- #C.1, N with 2,4-dichlorobenzenesulfonamide dichlorobenzenesulfonyl chloride and DIEA)2,5-Difluoro-N-((1S,3R)-3-(6-tosyl- N-((1S,3R)-3-(6H- H.1.84 1.29 (d)419 6H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-2,5- #C.1, N with2,5- difluorobenzenesulfonamide difluorobenzenesulfonyl chloride andDIEA) 4-Bromo-3-methyl-N-((1S,3R)-3-(6- N-((1S,3R)-3-(6H- H.1.85 1.36(d) 475 tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)benzenesulfonamide a]pyrazin-1- (prepared using I fromPreparation yl)cyclopentyl)-4-bromo-3- #C.1, N with 4-bromo-3-methylbenzenesulfonamide methylbenzenesulfonyl chloride and DIEA)2,3,4-Trifluoro-N-((1S,3R)-3-(6- N-((1S,3R)-3-(6H- H.1.86 1.31 (d) 437tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-2,3,4- #C.1, N with2,3,4- trifluorobenzenesulfonamide trifluorobenzenesulfonyl chloride andDIEA) 2,6-Difluoro-N-((1S,3R)-3-(6-tosyl- N-((1S,3R)-3-(6H- H.1.87 1.28(d) 419 6H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-2,6- #C.1, N with2,6- difluorobenzenesulfonamide difluorobenzenesulfonyl chloride andDIEA) 4-(Methylsulfonyl)-N-((1S,3R)-3- N-((1S,3R)-3-(6H- H.1.88 1.23 (d)461 (6-tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)benzenesulfonamide a]pyrazin-1- (prepared using I fromPreparation yl)cyclopentyl)-4- #C.1, N with 4-(methylsulfonyl)benzenesulfonamide (methylsulfonyl)benzenesulfonylchloride and DIEA) N-((1S,3R)-3-(6-Tosyl-6H- N-((1S,3R)-3-(6H- H.1.891.20 (d) 335 pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3-a]pyrazin-1- e][1,2,4]triazolo[4,3- yl)cyclopentyl)ethanesulfonamidea]pyrazin-1- (prepared using I from Preparationyl)cyclopentyl)ethanesulfonamide #C.1, N with ethanesulfonyl chlorideand DIEA) 2,4-Difluoro-N-((1S,3R)-3-(6-tosyl- N-((1S,3R)-3-(6H- H.1.901.30 (d) 419 6H-pyrrolo[2,3-i][1,2,4]triazolo[4,3- Pyrrolo[2,3-a]pyrazin-1- e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamidea]pyrazin-1- (prepared using I from Preparation yl)cyclopentyl)-2,4-#C.1, N with 2,4- difluorobenzenesulfonamide difluorobenzenesulfonylchloride and DIEA) N-((1S,3R)-3-(6-Tosyl-6H- N-((1S,3R)-3-(6H- H.1.911.23 (d) 349 pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3-a]pyrazin-1-yl)cyclopentyl)propane- e][1,2,4]triazolo[4,3- 1-sulfonamide(prepared using I a]pyrazin-1- from Preparation #C.1, N with 1-yl)cyclopentyl)propane-1- propanesulfonyl chloride and sulfonamide DIEA)2,5-Dichloro-N-((1S,3R)-3-(6-tosyl- N-((1S,3R)-3-(6H- H.1.92 1.35 (d)451 6H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-2,5- #C.1, N with2,5- dichlorobenzenesulfonamide dichlorobenzenesulfonyl chloride andDIEA) 1-Phenyl-N-((1S,3R)-3-(6-tosyl-6H- N-((1S,3R)-3-(6H- H.1.93 1.28(d) 397 pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)methanesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-1- #C.1, N withα-toluenesulfonyl phenylmethanesulfonamide chloride and DIEA)4-chloro-3-nitro-N-((1S,3R)-3-(6- N-((1S,3R)-3-(6H- H.1.94 1.33 (d) 462tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-4-chloro-3- #C.1, Nwith 4-chloro-3- nitrobenzenesulfonamide nitrobenzenesulfonyl chlorideand DIEA) 4-Nitro-N-((1S,3R)-3-(6-tosyl-6H- N-((1S,3R)-3-(6H- H.1.951.32 (d) 428 pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3-a]pyrazin-1- e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamidea]pyrazin-1- (prepared using I from Preparation yl)cyclopentyl)-4- #C.1,N with 4- nitrobenzenesulfonamide nitrobenzenesulfonyl chloride andDIEA) N-((1S,3R)-3-(6-Tosyl-6H- N-((1S,3R)-3-(6H- H.1.96 1.26 (d) 389pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)thiophene-2- a]pyrazin-1-sulfonamide (prepared using I from yl)cyclopentyl)thiophene-2-Preparation #C.1, N with thiophene- sulfonamide 2-sulfonyl chloride andDIEA) 5-Fluoro-2-methyl-N-((1S,3R)-3-(6- N-((1S,3R)-3-(6H- H.1.97 1.32(d) 415 tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)benzenesulfonamide a]pyrazin-1- (prepared using I fromPreparation yl)cyclopentyl)-5-fluoro-2- #C.1, N with 5-fluoro-2-methylbenzenesulfonamide methylbenzenesulfonyl chloride and DIEA)3-Nitro-N-((1S,3R)-3-(6-tosyl-6H- N-((1S,3R)-3-(6H- H.1.98 1.29 (d) 428pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-3- #C.1, N with 3-nitrobenzenesulfonamide nitrobenzenesulfonyl chloride and DIEA)N-(4-(N-((1S,3R)-3-(6-Tosyl-6H- N-(4-(N-((1S,3R)-3-(6H- H.1.99 1.19 (d)440 pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)sulfamoyl)phenyl)acetamidea]pyrazin-1- (prepared using I fromyl)cyclopentyl)sulfamoyl)phenyl)acetamide Preparation #C.1, N with N-acetylsulfanilyl chloride and DIEA) 2-Fluoro-N-((1S,3R)-3-(6-tosyl-6H-N-((1S,3R)-3-(6H- H.1.100 1.25 (d) 401pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-2- #C.1, N with 2-fluorobenzenesulfonamide fluorobenzenesulfonyl chloride and DIEA)5-Chloro-2-fluoro-N-((1S,3R)-3-(6- N-((1S,3R)-3-(6H- H.1.101 1.31 (d)435 tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)benzenesulfonamide a]pyrazin-1- (prepared using I fromPreparation yl)cyclopentyl)-5-chloro-2- #C.1, N with 5-chloro-2-fluorobenzenesulfonamide fluorobenzenesulfonyl chloride and DIEA)3-Fluoro-4-methyl-N-((1S,3R)-3-(6- N-((1S,3R)-3-(6H- H.1.102 1.30 (d)415 tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)benzenesulfonamide a]pyrazin-1- (prepared using I fromPreparation yl)cyclopentyl)-3-fluoro-4- #C.1, N with 3-fluoro-4-methylbenzenesulfonamide methylbenzenesulfonyl chloride and DIEA)4-Fluoro-N-((1S,3R)-3-(6-tosyl-6H- N-((1S,3R)-3-(6H- H.1.103 1.27 (d)401 pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)benzenesulfonamide a]pyrazin-1-(prepared using I from Preparation yl)cyclopentyl)-4- #C.1, N with 4-fluorobenzenesulfonamide fluorobenzenesulfonyl chloride and DIEA)N-((1S,3R)-3-(6-Tosyl-6H- N-((1S,3R)-3-(6H- H.1.104 1.30 (d) 433pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)naphthalene-1- a]pyrazin-1-sulfonamide (prepared using I from yl)cyclopentyl)naphthalene-Preparation #C.1, N with 1- 1-sulfonamide naphthalenesulfonyl chlorideand DIEA) N-((1S,3R)-3-(6-Tosyl-6H- N-((1S,3R)-3-(6H- H.1.105 1.31 (d)433 pyrrolo[2,3-e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)naphthalene-2- a]pyrazin-1-sulfonamide (prepared using I from yl)cyclopentyl)naphthalene-Preparation #C.1, N with 2- 2-sulfonamide naphthalenesulfonyl chlorideand DIEA) 4-Chloro-2-fluoro-N-((1S,3R)-3-(6- N-((1S,3R)-3-(6H- H.1.1061.31 (d) 435 tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)benzenesulfonamide a]pyrazin-1- (prepared using I fromPreparation yl)cyclopentyl)-4-chloro-2- #C.1, N with 4-chloro-2-fluorobenzenesulfonamide fluorobenzenesulfonyl chloride and DIEA)4-Fluoro-2-methyl-N-((1S,3R)-3-(6- N-((1S,3R)-3-(6H- H.1.107 1.29 (d)415 tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)benzenesulfonamide a]pyrazin-1- (prepared using I fromPreparation yl)cyclopentyl)-4-fluoro-2- #C.1, N with 4-fluoro-2-methylbenzenesulfonamide methylbenzenesulfonyl chloride and DIEA)2-Fluoro-5-methyl-N-((1S,3R)-3-(6- N-((1S,3R)-3-(6H- H.1.108 1.28 (d)415 tosyl-6H-pyrrolo[2,3- Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)benzenesulfonamide a]pyrazin-1- (prepared using I fromPreparation yl)cyclopentyl)-2-fluoro-5- #C.1, N with 2-fluoro-5-methylbenzenesulfonamide methylbenzenesulfonyl chloride and DIEA)2,5-Dichloro-N-((1S,3R)-3-(6-tosyl- N-((1S,3R)-3-(6H- H.1.109 1.34 (d)457 6H-pyrrolo[2,3- Pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)thiophene-3- a]pyrazin-1-sulfonamide (prepared using I from yl)cyclopentyl)-2,5- Preparation#C.1, N with 2,5- dichlorothiophene-3- dichlorothiophene-3-sulfonylsulfonamide chloride and DIEA)General Procedure I: Acidic Cleavage of a Boc-Protected Amine

To a solution of a Boc-protected amine (preferably 1 equiv) in anorganic solvent (such as DCM, 1,4-dioxane, or MeOH) is added TFA or HCl(preferably 4 N HCl in 1,4-dioxane solution, 2-35 equiv, preferably 2-15equiv). The reaction is stirred at about 20-100° C. (preferably ambienttemperature to about 60° C.) for about 1-24 h (preferably about 1-6 h).Optionally additional TFA or HCl (preferably 4 N HCl in 1,4-dioxanesolution, 2-35 equiv, preferably 2-15 equiv) may be added to thereaction mixture in cases where the reaction does not proceed tocompletion as monitored by TLC, LC/MS, or HPLC. The reaction is thencontinued at ambient temperature or optionally heated up to about 100°C. (preferably heated at about 60° C.) for about 1-24 h (preferablyabout 1-6 h). If a solid is present in the reaction mixture, thereaction mixture may be filtered and the solid washed with an organicsolvent such as 1,4-dioxane or Et₂O. The resulting solid is thenoptionally dried under reduced pressure. Alternatively, the filteredmaterial may be partitioned between an organic solvent (such as EtOAc,DCM or 1,4-dioxane) and an aqueous base (such as saturated aqueousNaHCO₃ or saturated aqueous Na₂CO₃, preferably saturated aqueousNaHCO₃). The mixture is stirred for about 1-5 h (preferably about 1 h).Any insoluble material is collected by filtration and may be washed witha suitable solvent (such as cold water and/or Et₂O) then may beoptionally dried under reduced pressure. The organic layer mayoptionally be washed with brine, dried over anhydrous Na₂SO₄ or MgSO₄,then decanted or filtered, prior to concentrating under reduced pressureto give the target compound. Alternatively, the reaction is partitionedbetween a basic aqueous solution (such as Na₂CO₃, NaHCO₃ or NaOH,preferably NaOH) and an organic solvent (such as EtOAc or DCM). Theaqueous layer is then optionally extracted with additional organicsolvent such as EtOAc or DCM. The combined organic layers may optionallybe washed with brine, dried over anhydrous Na₂SO₄ or MgSO₄, thendecanted or filtered, prior to concentrating under reduced pressure togive the target compound. Optionally, the crude material is purified bychromatography, trituration with an appropriate solvent, orcrystallization from one or more solvents to give the target compound.

Example #I.1.1(R)-1-(Piperidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazinehydrochloride

A round bottom flask was charged with (R)-tert-butyl3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidine-1-carboxylate(0.92 g, 2.68 mmol; prepared using A from Preparation #9,(R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid [CNHTechnologies], EDC and TEA, and E using SOCl₂, TEA, and saturatedaqueous Na₂CO₃), HCl (4 N in 1,4-dioxane, 2.9 mL, 11.5 mmol), and1,4-dioxane (20 mL). The reaction mixture was heated at about 60° C. forabout 3 h. The reaction mixture was cooled to ambient temperature thenfiltered under vacuum and washed with Et₂O (35 mL). The solid was thendried for about 16 h in a heated vacuum oven (at about 70° C.) to give(R)-1-(piperidin-3-yl)-6H-pyrrolo[2,3-e][1, 2, 4]triazolo[4,3-a]pyrazinehydrochloride as a brown solid (0.69 g, 82%): LC/MS (Table 2, Method a)R_(t)=0.45 min; MS m/z 243 (M+H)⁺.

TABLE I.1 Examples prepared using General Procedure I R_(t) min (Table2, m/z ESI+ Boc-protected Amine Product Example # Method) (M + H)⁺tert-Butyl (1S,3S)-3-(6H-pyrrolo[2,3- (1S,3S)-3-(6H- I.1.2 0.50 (d) 243e][1,2,4]triazolo[4,3-a]pyrazin-1- Pyrrolo[2,3- yl)cyclopentylcarbamate(prepared e][1,2,4]triazolo[4,3- using A from (1S,3S)-3-(tert-a]pyrazin-1- butoxycarbonylamino)cyclopentane- yl)cyclopentanaminecarboxylic acid [Acros] and hydrochloride Preparation #9, E)(S)-tert-Butyl 3-(6H-pyrrolo[2,3- (S)-1-(Piperidin-3- I.1.3 0.86 (a) 243e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)-6H-pyrrolo[2,3-yl)piperidine-1-carboxylate (prepared e][1,2,4]triazolo[4,3- using Afrom Preparation #3 and (S)- a]pyrazine1-(tert-butoxycarbonyl)piperidine-3- carboxylic acid, EDC•HCl, and TEA,C with DIEA, and H) tert-Butyl trans-3-(6H-pyrrolo[2,3- trans-3-(6H-I.1.4 0.70 (a) 229 e][1,2,4]triazolo[4,3-a]pyrazin-1- Pyrrolo[2,3-yl)cyclobutylcarbamate, (prepared e][1,2,4]triazolo[4,3- using A from3-(tert- a]pyrazin-1- butoxycarbonylamino)cyclobutane-yl)cyclobutanamine carboxylic acid [AMRI] and hydrochloride Preparation# 9, E) (R)-tert-Butyl 3-(6H-pyrrolo[2,3- (R)-1-(Pyrrolidin-3- I.1.50.67 (a) 229 e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)-6H-pyrrolo[2,3-yl)pyrrolidine-1-carboxylate, e][1,2,4]triazolo[4,3- (prepared using Afrom (R)-1-(tert- a]pyrazine butoxycarbonyl)pyrrolidine-3- hydrochloridecarboxylic acid [Astatech] and Preparation # 9, E) tert-Butyl4-methyl-3-(6H- 1-(4- I.1.6 1.01 (a) 257pyrrolo[2,3-e][1,2,4]triazolo[4,3- Methylpiperidin-3-a]pyrazin-1-yl)piperidine-1- yl)-6H-pyrrolo[2,3- carboxylate (preparedusing Y from e][1,2,4]triazolo[4,3- 4-methylnicotinic acid, R, P, S, T,a]pyrazine and G from Preparation #9) hydrochloride (S)-tert-Butyl3-(6H-pyrrolo[2,3- (S)-1-(Pyrrolidin-3- I.1.7 0.85 (a) 227e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)-6H-pyrrolo[2,3-yl)pyrrolidine-1-carboxylate e][1,2,4]triazolo[4,3- (prepared using Afrom Preparation a]pyrazine #9, (S)-1-(tert- hydrochloridebutoxycarbonyl)pyrrolidine-3- carboxylic acid [CHEM-IMPEX] and EDC•HCl,E with TEA and NaOH) tert-Butyl 2-(6H-imidazo[1,5- 2-(6H-Imidazo[1,5-I.1.8 0.84 (d) 202 a]pyrrolo[2,3-e]pyrazin-1- a]pyrrolo[2,3-yl)ethylcarbamate (prepared using L e]pyrazin-1- from Example #13, StepF and 3-(tert- yl)ethanamine butoxycarbonylamino)propanoic acidhydrochloride with HATU and TEA, AA with Belleau's reagent, H, I withHCl (g)) tert-Butyl-2-methyl-3-(6H- 1-(2- I.1.9 0.81 (a) 257pyrrolo[2,3-e][1,2,4]triazolo[4,3- Methylpiperidin-3-a]pyrazin-1-yl)piperidine-1- yl)-6H-pyrrolo[2,3- carboxylate (preparedusing R from e][1,2,4]triazolo[4,3- ethyl 2-methylnicotinate, P, S, T, Ga]pyrazine from Preparation #9) hydrochloride tert-Butyl 3-methyl-5-(6H-1-(5- I.1.10 1.05 (a) 257 pyrrolo[2,3-e][1,2,4]triazolo[4,3-Methylpiperidin-3- a]pyrazin-1-yl)piperidine-1- yl)-6H-pyrrolo[2,3-carboxylate (prepared using R from e][1,2,4]triazolo[4,3- methyl5-methylnicotinate [Alfa], P, a]pyrazine S, T, G from Preparation #9)hydrochlorideGeneral Procedure J: Deprotection of a Cbz-Protected Amine

A mixture of an O-benzylcarbamate (preferably 1 equiv) and 10% Pd oncarbon (0.05-0.30 equiv, preferably 0.10 equiv) in a protic solvent(such as MeOH, EtOH, AcOH, preferably EtOH) is shaken or stirred underhydrogen at about 15-100 psi (preferably about 60 psi) for about 4-48 h(preferably about 4-16 h) at ambient temperature. The reaction isfiltered through Celite® and concentrated to dryness under reducedpressure. The crude material is optionally purified by precipitation,crystallization, and/or trituration from an appropriate solvent orsolvents and/or by chromatography to give the target compound.

Illustration of General Procedure J

Example #J.1.11-(Piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

Benzyl4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidine-1-carboxylate(0.34 g, 0.90 mmol, Example #2, Step A) and 10% Pd on carbon (0.10 g,0.09 mmol) in MeOH (30 mL) was shaken under hydrogen at about 60 psi forabout 5 h at ambient temperature. The reaction was filtered throughCelite® and concentrated under reduced pressure to constant weight toafford1-(piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine as ayellow solid (0.18 g, 77%): LC/MS (Table 2, Method a) R_(t)=0.70 min; MSm/z: 243 (M+H)⁺.

TABLE J.1 Examples prepared using General Procedure J R_(t) min (Table2, m/z ESI+ Cbz-protected Amine Product Example # Method) (M + H)⁺Benzyl 4-methyl-3-(6H- 1-(4-Methylpiperidin-3- J.1.2 1.03 (a) 257pyrrolo[2,3-e][1,2,4]triazolo[4,3- yl)-6H-pyrrolo[2,3-a]pyrazin-1-yl)piperidine-1- e][1,2,4]triazolo[4,3- carboxylate(prepared using R a]pyrazine [major from 4-methylnicotinic acid, Q,product] W and B from Preparation #3) Benzyl 4-methyl-3-(6H- 1-(1,3-J.1.3 0.71 (a) 271 pyrrolo[2,3-e][1,2,4]triazolo[4,3-Dimethylpiperidin-4- a]pyrazin-1-yl)piperidine-1- yl)-6H-pyrrolo[2,3-carboxylate (prepared using R e][1,2,4]triazolo[4,3- from4-methylnicotinic acid, Q, a]pyrazine acetate W and B from Preparation#3) [minor product] Benzyl cis-3-(6H-pyrrolo[2,3-cis-3-(6H-Pyrrolo[2,3 - J.1.4 0.56 (a) 229e][1,2,4]triazolo[4,3-a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclobutylcarbamate a]pyrazin-1- (prepared using Q from 3-yl)cyclobutanamine aminocyclobutanecarboxylic acid hydrochloride[Enamine], A from Preparation # 9, E)General Procedure K: Formation of an Amide from an Activated Acid and anAmine

To a round-bottomed flask containing an amine or an amine salt(preferably 1 equiv) in an organic solvent (such as DCM, DMF, or1,4-dioxane, preferably DCM or DMF) is added an organic base such asDIEA or TEA (0-5 equiv, preferably 3 equiv). The reaction mixture isoptionally made homogeneous by heating or sonicating (preferably bysonicating). To the reaction mixture is added an activated acid (such asa perfluorophenyl ester derivative or an acid chloride). The resultingmixture is stirred at ambient temperature for about 1-24 h (preferablyabout 16 h). The reaction mixture may be directly purified bychromatography. Alternatively, the solvent is concentrated under reducedpressure or a suitable organic solvent (such as EtOAc or DCM) is addedand the solution is washed with water or brine. The layers are separatedand the organic solution is optionally dried over anhydrous Na₂SO₄ orMgSO₄, filtered or decanted, and concentrated to dryness under reducedpressure. The crude material is optionally purified by precipitation,crystallization, and/or trituration from an appropriate solvent orsolvents and/or by chromatography to give the target compound.

Illustration of General Procedure K

Example #K.1.1N-(cis-4-(6H-Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexyl)-2-cyanoacetamide

To a suspension ofcis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanaminehydrochloride (0.106 g, 0.206 mmol, Example #D.1) in DCM (4 mL) wasadded TEA (0.086 mL, 0.62 mmol). The reaction mixture was sonicateduntil the reaction was homogeneous. To the reaction solution was addedperfluorophenyl 2-cyanoacetate (0.078 g, 0.31 mmol, Preparation #6). Theresulting solution was stirred at ambient temperature for about 16 h.The crude reaction mixture was purified by silica gel chromatography (40g) eluting with a gradient of 0-20% EtOAc in DCM and then furtherpurified by RP-HPLC (Table 2, Method e) to giveN-(cis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexyl)-2-cyanoacetamidewith 3 equiv NH₄OAc as an excipient (0.025 g, 22%). LC/MS (Table 2,Method a) R_(t)=1.33 min; MS m/z: 324 (M+H)⁺.

TABLE K.1 Examples prepared from perfluorophenyl 2-cyanoacetate(Preparation #6) using General Procedure K R_(t) min (Table 2, m/z ESI+Amine Product Ex. # Method) (M + H)⁺ (1R,3S)-3-(6H-Pyrrolo[2,3-N-((1R,3S)-3-(6H- K.1.2 1.27 (a) 310 e][1,2,4]triazolo[4,3-a]pyrazin-1-Pyrrolo[2,3- yl)cyclopentanamine e][1,2,4]triazolo[4,3- hydrochloride(Example #D.1.2) a]pyrazin-1- yl)cyclopentyl)-2- cyanoacetamidetrans-4-(6H-Pyrrolo[2,3- N-(trans-4-(6H- K.1.3 1.35 (a) 324e][1,2,4]triazolo[4,3-a]pyrazin-1- Pyrrolo[2,3- yl)cyclohexanaminee][1,2,4]triazolo[4,3- hydrochloride (Example #D.1.3) a]pyrazin-1-yl)cyclohexyl)-2- cyanoacetamide (1R,3R)-3-(6H-Pyrrolo[2,3-N-((1R,3R)-3-(6H- K.1.4 1.39 (a) 310 e][1,2,4]triazolo[4,3-a]pyrazin-1-Pyrrolo[2,3- yl)cyclopentanamine e][1,2,4]triazolo[4,3- hydrochloride(Example #D.1.4) a]pyrazin-1- yl)cyclopentyl)-2- cyanoacetamide((1S,3R)-3-(6H-Pyrrolo[2,3- N-((1S,3R)-3-(6H- K.1.5 1.38 (a) 310e][1,2,4]triazolo[4,3-a]pyrazin-1- Pyrrolo[2,3- yl)cyclopentanaminee][1,2,4]triazolo[4,3- hydrochloride (Example #6, Step a]pyrazin-1- C)yl)cyclopentyl)-2- cyanoacetamide (1S,3S)-3-(6H-Pyrrolo[2,3-N-((1S,3S)-3-(6H- K.1.6 1.05 (d) 310 e][1,2,4]triazolo[4,3-a]pyrazin-1-Pyrrolo[2,3- yl)cyclopentanamine e][1,2,4]triazolo[4,3- hydrochloride(Example #I.1.2) a]pyrazin-1- yl)cyclopentyl)-2- cyanoacetamideGeneral Procedure L: Formation of an Amide from a Carboxylic Acid and anAmine

To a solution or suspension of a carboxylic acid (1-5 equiv, preferably1.5 equiv) and an amine (1-5 equiv, preferably 1 equiv) in an organicsolvent (such as DCM, DCE, THF, or 1,4-dioxane, preferably DCM) is addeda peptide coupling reagent (such as BOP-Cl, IBCF, HATU, or EDC.HCl,preferably EDC.HCl, 1-10 equiv, preferably 1-10 equiv), a base (such asTEA, DIEA, or pyridine, preferably TEA, 0-20 equiv, preferably 2 equiv)and HOBt (0-5 equiv, preferably 0-1 equiv when EDC.HCl is used). Thereaction mixture is then stirred at ambient temperature for about 15 minto 24 h (preferably about 16 h). The reaction mixture is then worked upusing one of the following methods. Method 1: The reaction mixture isdiluted with water or saturated aqueous NaHCO₃. The layers areseparated. The aqueous layer is optionally extracted with additionalorganic solvent such as EtOAc or DCM. The organic layer is (or combinedlayers are) optionally washed with water, saturated aqueous NaHCO₃and/or brine, dried over anhydrous MgSO₄ or Na₂SO₄, filtered ordecanted, and concentrated under reduced pressure. Method 2: The crudereaction mixture is filtered through a pad of silica gel, washing with asuitable solvent (such as EtOAc, MeOH, or DCM, preferably MeOH), andconcentrated under reduced pressure. Method 3: The crude reactionmixture is directly purified by chromatography without a work up. In allcases, the crude material is optionally further purified byprecipitation, crystallization, and/or trituration from an appropriatesolvent or solvents and/or by chromatography to give the targetcompound.

Illustration of General Procedure L

Example #L.1.1(R)-3-(3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidin-1-yl)-3-oxopropanenitrile

To a suspension of(R)-1-(piperidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazinehydrochloride (0.074 g, 0.265 mmol; Example #I1.1) and 2-cyanoaceticacid (0.034 g, 0.398 mmol) in DMF (3 mL) was added HOBt (0.041 g, 0.265mmol), EDC.HCl (0.051 g, 0.265 mmol) and DIEA (0.093 mL, 0.531 mmol).The reaction mixture was stirred at ambient temperature for about 16 h.The crude reaction mixture was purified by RP-HPLC (Table 2, Method f).The appropriate fractions were concentrated in vacuo and lyophilized toafford(R)-3-(3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidin-1-yl)-3-oxopropanenitrileas a white solid (0.052 g, 63%): LC/MS (Table 2, Method a) R_(t)=1.30min; MS m/z: 310 (M+H)⁺.

TABLE L.1 Examples prepared from(R)-1-(piperidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4] triazolo[4,3-a]pyrazine(Example #I.1.1) using General Procedure L R_(t) min (Table 2, m/z ESI+Carboxylic Acid Product Ex. # Method) (M + H)⁺ 3,3,3-(R)-1-(3-(6H-Pyrrolo[2,3- L.1.2 1.53 (a) 353 Trifluoropropanoice][1,2,4]triazolo[4,3-a]pyrazin-1- acid yl)piperidin-1-yl)-3,3,3-trifluoropropan-1-one 1- (R)-1-(3-(6H-Pyrrolo[2,3- L.1.3 1.48 (a) 336Cyanocyclopropane- e][1,2,4]triazolo[4,3-a]pyrazin-1- carboxylic acidyl)piperidine-1- carbonyl)cyclopropanecarbonitrile (R)-2-(R)-4-((R)-3-(6H-Pyrrolo[2,3- L.1.4 1.33 (a) 372 Oxothiazolidine-4-e][1,2,4]triazolo[4,3-a]pyrazin-1- carboxylic acid yl)piperidine-1-carbonyl)thiazolidin-2-one 4-Cyanobenzoic acid (R)-4-(3-(6H-Pyrrolo[2,3-L.1.5 1.53 (a) 372 e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)piperidine-1-carbonyl)benzonitrile

TABLE L.2 Examples prepared fromcis-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanamine acetate (prepared using A from Preparation#3 and cis-3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid[AMRI]; F) using General Procedure L R_(t) min (Table 2, m/z ESI+Carboxylic Acid Product Ex. # Method) (M + H)⁺ 2-Cyanoacetic acidN-(cis-3-(6H-Pyrrolo[2,3- L.2.1 1.40 (a) 324e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclohexyl)-2-cyanoacetamideAcetic acid N-(cis-3-(6H-Pyrrolo[2,3- L.2.2 1.32 (a) 299e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclohexyl)acetamide

TABLE L.3 Additional examples prepared from 2-cyanoacetic acid usingGeneral Procedure L R_(t) min (Table 2, m/z ESI+ Amine Product Ex. #Method) (M + H)⁺ (S)-1-(Piperidin-3-yl)-6H- (S)-3-(3-(6H-Pyrrolo[2,3-L.3.1 1.34 (a) 310 pyrrolo[2,3- e][1,2,4]triazolo[4,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)piperidin-1- a]pyrazine (Example #I.1.3) yl)-3-oxopropanenitrile 1-(4-Methylpiperidin-3-yl)-3-(4-Methyl-3-(6H- L.3.2 1.42 (a) 342 6H-pyrrolo[2,3- pyrrolo[2,3-e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3- a]pyrazine (Example#J.1.2) a]pyrazin-1-yl)piperidin-1- yl)-3-oxopropanenitrilecis-3-(6H-Pyrrolo[2,3- N-(cis-3-(6H-Pyrrolo[2,3- L.3.3 1.23 (a) 296e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-a]pyrazin-1-yl)cyclobutyl)- yl)cyclobutanamine (Example 2-cyanoacetamide#J.1.4) trans-3-(6H-Pyrrolo[2,3- N-(trans-3-(6H-Pyrrolo[2,3- L.3.4 1.05(a) 296 e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-a]pyrazin-1-yl)cyclobutyl)- yl)cyclobutanamine 2-cyanoacetamidehydrochloride (Example #I.1.4) (R)-1-(Pyrrolidin-3-yl)-6H-(R)-3-(3-(6H-Pyrrolo[2,3- L.3.5 1.00 (a) 296 pyrrolo[2,3-e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidin-1- a]pyrazine hydrochlorideyl)-3-oxopropanenitrile (Example #I.1.5) (S)-1-(Pyrrolidin-3-yl)-6H-(S)-3-(3-(6H-Pyrrolo[2,3- L.3.6 1.19 (a) 296 pyrrolo[2,3-e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidin-1- a]pyrazine hydrochlorideyl)-3-oxopropanenitrile (Example #I.1.7) (R)-1-(Piperidin-3-yl)-6H-(R)-1-(3-(6H-Imidazo[1,5- L.3.7 1.61 (a) 335 imidazo[1,5-a]pyrrolo[2,3-a]pyrrolo[2,3-e]pyrazin-1- e]pyrazine (prepared using L yl)piperidine-1-from Example #13, Step F carbonyl)cyclopropane- and (R)-1-(tert-carbonitrile butoxycarbonyl)piperidine-3- carboxylic acid, HATU and TEA,AA with Belleau's reagent, H, I with 4 N HCl in 1,4-dioxane)2-(6H-Imidazo[1,5- N-(2-(6H-Imidazo[1,5- L.3.8 1.39 (a) 295a]pyrrolo[2,3-e]pyrazin-1- a]pyrrolo[2,3-e]pyrazin-1- yl)ethanaminehydrochloride yl)ethyl)-1- (Example #I.1.8) cyanocyclopropane-carboxamide 1-(5-Methylpiperidin-3-yl)- 3-(3-Methyl-5-(6H- L.3.9 1.52(a) 324 6H-pyrrolo[2,3- pyrrolo[2,3- e][1,2,4]triazolo[4,3-e][1,2,4]triazolo[4,3- a]pyrazine hydrochloridea]pyrazin-1-yl)piperidin-1- (Example #I.1.10) yl)-3-oxopropanenitrile1-(4-Methylpiperidin-3-yl)- 3-(3-(6H-Imidazo[1,5- L.3.10 1.42 (a) 3236H-imidazo[1,5- a]pyrrolo[2,3-e]pyrazin-1- a]pyrrolo[2,3-e]pyrazineyl)-4-methylpiperidin-1-yl)- hydrochloride (Example #13,3-oxopropanenitrile Step K)

TABLE L.4 Examples prepared from 1-cyanocyclopropanecarboxylic acidusing General Procedure L R_(t) min (Table 2, m/z ESI+ Amine Product Ex.# Method) (M + H)⁺ ((1R,3R)-3-(6H-Pyrrolo[2,3- N-(((1R,3R)-3-(6H- L.4.11.56 (a) 350 e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentyl)methanamine a]pyrazin-1-hydrochloride (Example yl)cyclopentyl)methyl)-1- #F.1.1)cyanocyclopropane- carboxamide 1-(4-Methylpiperidin-3-yl)-1-((3S,4S)-4-Methyl-3- L.4.2 1.61 (a) 350 6H-pyrrolo[2,3-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3-a]pyrazine hydrochloride a]pyrazin-1-yl)piperidine- (Example #I.1.6)1-carbonyl)cyclopropane- carbonitrile 1-(4-Methylpiperidin-3-yl)-1-((3R,4R)-4-Methyl-3- L.4.3 1.61 (a) 350 6H-pyrrolo[2,3-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3-a]pyrazine hydrochloride a]pyrazin-1-yl)piperidine- (Example #I.1.6)1-carbonyl)cyclopropane- carbonitrile 1-(4-Methylpiperidin-3-yl)-1-((3S,4R)-4-Methyl-3- L.4.4 1.61 (a) 350 6H-pyrrolo[2,3-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3-a]pyrazine hydrochloride a]pyrazin-1-yl)piperidine- (Example #I.1.6)1-carbonyl)cyclopropane- carbonitrile 1-(4-Methylpiperidin-3-yl)-1-((3R,4S)-4-Methyl-3- L.4.5 1.61 (a) 350 6H-pyrrolo[2,3-(6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3-a]pyrazine hydrochloride a]pyrazin-1-yl)piperidine- (Example #I.1.6)1-carbonyl)cyclopropane- carbonitrile 8-((3S,4S)-4-Methylpiperidin-3-((3S,4S)-3-(3H- L.4.6 1.35 (a) 323 3-yl)-3H-imidazo[1,2- Imidazo[1,2-a]pyrrolo[2,3-e]pyrazine and a]pyrrolo[2,3-e]pyrazin-8-((3R,4R)-4-methylpiperidin- 8-yl)-4-methylpiperidin-3-yl)-3H-imidazo[1,2- 1-yl)-3-oxopropanenitrile a]pyrrolo[2,3-e]pyrazineand -((3R,4R)-3-(3H- (prepared using H from imidazo[1,2- Preparation#19) a]pyrrolo[2,3-e]pyrazin- 8-yl)-4-methylpiperidin-1-yl)-3-oxopropanenitrile 1-(2-Methylpiperidin-3-yl)- 1-(2-Methyl-3-(6H-L.4.7 1.57 (a) 350 6H-pyrrolo[2,3- pyrrolo[2,3- e][1,2,4]triazolo[4,3-e][1,2,4]triazolo[4,3- a]pyrazine hydrochloridea]pyrazin-1-yl)piperidine- (Example #I.1.9) 1-carbonyl)cyclopropanecarbonitrile

TABLE L.5 Examples prepared fromtrans-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanamine acetate (Example #F.1.2) using GeneralProcedure L R_(t) min (Table 2, m/z ESI+ Carboxylic Acid Product Ex. #Method) (M + H)⁺ 2-Cyanoacetic acid N-(trans-3-(6H-Pyrrolo[2,3- L.5.11.42 (a) 324 e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexyl)-2-cyanoacetamide Acetic acid N-(trans-3-(6H-Pyrrolo[2,3-L.5.2 1.33 (a) 299 e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexyl)acetamide

TABLE L.6 Example prepared from(R)-1-(1-methylpiperazin-2-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine hydrochloride (prepared using A fromPreparation #9 and Preparation #16, C with TEA, H, I with 4 N HCl in1,4-dioxane) using General Procedure L R_(t) min Carboxylic (Table 2,m/z ESI+ acid Product Ex. # Method) (M + H)⁺ 2-(R)-3-(4-Methyl-3-(6H-pyrrolo[2,3- L.6.1 1.30 (a) 325 Cyanoacetice][1,2,4]triazolo[4,3-a]pyrazin-1- acidyl)piperazin-1-yl)-3-oxopropanenitrileGeneral Procedure M: Formation of a Urea from an Amine and a CarbamoylChloride

To a flask containing an amine or an amine salt (1 equiv) in an organicsolvent (such as THF, or 1,4-dioxane, preferably THF) is added a base(such as DIEA or TEA, preferably TEA (3-5 equiv, preferably 3 equiv) andstirred at ambient temperature for about 0-30 min (preferably about 5min) then added a carbamoyl chloride (0.5-2 equiv, preferably 0.75equiv). The mixture is stirred at about 0-90° C. (preferably about60-65° C.) for about 2-24 h (preferably about 16 h). The reactionmixture is allowed to reach ambient temperature. The organic solvent isoptionally removed under reduced pressure. The crude material can bepartitioned between an organic solvent (such as EtOAc or DCM) and water,an aqueous base (such as saturated aqueous NaHCO₃) or brine. The layersare separated and the organic layer is optionally washed with water, anaqueous base (such as saturated aqueous NaHCO₃) and/or brine, dried overanhydrous Na₂SO₄ or MgSO₄, filtered, and concentrated under reducedpressure to give the target compound. The crude material is optionallypurified by precipitation crystallization or trituration from anappropriate solvent or solvents or by chromatography to give the targetcompound.

Illustration of General Procedure M

Example #M.1.1N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)pyrrolidine-1-carboxamide

A round bottom flask was charged with(1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanaminehydrochloride (0.150 g, 0.62 mmol, Example #D.1.4) and TEA (0.26 mL, 1.9mmol) in THF (5.7 mL). The reaction mixture was stirred for about 5 minat ambient temperature before pyrrolidine-1-carbonyl chloride (0.052 mL,0.46 mmol) was added. The reaction was heated at about 60° C. for about16 h, cooled to ambient temperature, and concentrated under reducedpressure. The crude product was dissolved in DCM (40 mL) and washed withsaturated aqueous NaHCO₃ (20 mL), brine (20 mL), dried over anhydrousMgSO₄, filtered and concentrated under reduced pressure. The materialwas purified by RP-HPLC (Table 2, Method i). The appropriate fractionswere combined, the solvent was mostly removed under reduced pressure,and the solid was filtered and dried under lyophilization to giveN-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)pyrrolidine-1-carboxamide(0.018 g, 8%): LC/MS (Table 2, Method a) R_(t)=1.40 min; MS m/z 340(M+H)⁺.

TABLE M.1 Examples prepared from pyrrolidine-1-carbonyl chloride usingGeneral Procedure M R_(t) min (Table 2, m/z ESI+ Amine Product Ex. #Method) (M + H)⁺ (R)-1-(Piperidin-3-yl)-6H- (R)-(3-(6H-Pyrrolo[2,3-M.1.2 1.44 (a) 340 pyrrolo[2,3- e][1,2,4]triazolo[4,3-e][1,2,4]triazolo[4,3- a]pyrazin-1-yl)piperidin-1- a]pyrazinehydrochoride yl)(pyrrolidin-1-yl)methanone (Example #I.1.1)(1S,3R)-3-(6H-Pyrrolo[2,3- N-((1S,3R)-3-(6H- M.1.3 1.47 (a) 340e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentanamine a]pyrazin-1- hydrochloride (Example #6,yl)cyclopentyl)pyrrolidine-1- Step C) carboxamideGeneral Procedure N: Formation of a Sulfonamide from an Amine

To a mixture or a solution (preferably a solution) of an amine or anamine salt (preferably 1 equiv) in a solvent such as THF, DCM or DMF(preferably DMF) is added an organic base such as TEA or DIEA (1-10equiv, preferably 2-4 equiv) or an aqueous base such as saturatedaqueous NaHCO₃ (5-20 equiv, preferably 5-10 equiv) (preferably anorganic base) and a sulfonyl chloride (0.85-3 equiv, preferably 1-1.5equiv). The reaction is stirred at −10-80° C. (preferably at ambienttemperature) for about 0.5-72 h (preferably about 1-2 h). Optionally,additional base (1-10 equiv) and/or sulfonyl chloride (0.4-2 equiv) maybe added at any point during the reaction time. The reaction is workedup using one of the following methods. Method 1: The reaction is dilutedwith water and extracted with an organic solvent such as DCM or EtOAc.The combined organic layers are optionally washed with brine, dried overanhydrous Na₂SO₄ or MgSO₄, filtered or decanted, and concentrated underreduced pressure. Method 2: The crude reaction mixture is purified bypreparative HPLC directly or after the addition of organic solvent suchas MeOH or DMF or an aqueous buffer such as 50 mM NH₄OAc with or withoutconcentrating the mixture under reduced pressure first. Method 3: Thereaction is diluted with an organic solvent such as DCM or EtOAc andwashed with water and/or brine. The organic layer is optionally driedover anhydrous Na₂SO₄ or MgSO₄, filtered or decanted, and concentratedunder reduced pressure. Method 4: The reaction is diluted with water andthe resulting solid is collected by vacuum filtration. In all cases, thecrude material is optionally purified by precipitation, crystallization,and/or trituration from an appropriate solvent or solvents and/or bychromatography to give the target compound.

Illustration of General Procedure N

Example #N.1.1N-((1S,3R)-3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide

To a mixture of(1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanaminehydrochloride (0.300 g, 0.952 mmol, Example #6, Step C) in DMF (9 mL)was added TEA (0.462 mL, 3.33 mmol) and cyclopropanesulfonyl chloride(0.097 mL, 0.95 mmol). After about 1.5 h at ambient temperature, thereaction was diluted with water (10 mL) and extracted with DCM (3×15mL). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Tothe crude material was added MeOH (˜50 mL) and a small amount ofinsoluble material (<0.01 g) was removed by filtration. Silica gel (2 g)was added to the filtrate and the mixture was concentrated under reducedpressure. The mixture was purified by silica gel chromatography elutingwith a step-wise gradient of DCM/MeOH/NH₄OH 990:9:1 to 980:18:2 to givean off-white solid that was dried in a vacuum oven at about 70° C. Thesolid was dissolved in hot MeOH, filtered while hot to removeparticulates and then the filtrate was sonicated while cooling toprovide a fine suspension which was concentrated under reduced pressureand dried in a vacuum oven at about 100° C. to give N-((1S,3R)-3-(6H-pyrrolo[2,3-e][1, 2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.21g, 64%): LC/MS (Table 2, Method a) R_(t)=1.51 min; MS m/z: 347 (M+H)⁺.

TABLE N.1 Examples prepared with cyclopropylsulfonyl chloride usingGeneral Procedure N R_(t) min (Table 2, m/z ESI+ Amine Product Ex. #Method) (M + H)⁺ (R)-1-(6H-Pyrrolo[2,3- (R)—N-(1-(6H-Pyrrolo[2,3- N.1.21.42 (a) 348 e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)pyrrolidin-3- a]pyrazin-1-yl)pyrrolidin-3- amine(prepared using U from yl)cyclopropane-sulfonamide Preparation #9 andPreparation #10, V, H) trans-4-(6H-Pyrrolo[2,3-N-(trans-4-(6H-Pyrrolo[2,3- N.1.3 1.24 (a) 361 e][1,2,4]triazolo[4,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- a]pyrazin-1- yl)cyclohexanamineyl)cyclohexyl)cyclopropanesulfonamide hydrochloride (Example #D.1.3)cis-4-(6H-Pyrrolo[2,3- N-(cis-4-(6H-Pyrrolo[2,3- N.1.4 1.54 (a) 361e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3- a]pyrazin-1- a]pyrazin-1-yl)cyclohexanamine yl)cyclohexyl)cyclopropanesulfonamide hydrochloride(Example #D.1.1) (1R,3S)-3-(6H-Pyrrolo[2,3- N-((1R,3S)-3-(6H- N.1.5 1.20(a) 347 e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1-yl)cyclo-e][1,2,4]triazolo[4,3- pentanamine hydrochloride a]pyrazin-1- (Example#D.1.2) yl)cyclopentyl)cyclopropanesulfonamide(1R,3R)-3-(6H-Pyrrolo[2,3- N-((1R,3R)-3-(6H- N.1.6 1.48 (a) 347e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentanamine a]pyrazin-1- hydrochloride (Exampleyl)cyclopentyl)cyclopropanesulfonamide #D.1.4)(1S,3S)-3-(6H-Pyrrolo[2,3- N-((1S,3S)-3-(6H-Pyrrolo[2,3- N.1.7 1.11 (d)347 e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-a]pyrazin-1- yl)cyclopentanamine yl)cyclopentyl)cyclopropanesulfonamidehydrochloride (Example # I.1.2) trans-3-(6H-Pyrrolo[2,3-N-(trans-3-(6H-Pyrrolo[2,3- N.1.8 1.34 (a) 361 e][1,2,4]triazolo[4,3-e][1,2,4]triazolo[4,3- a]pyrazin-1- a]pyrazin-1- yl)cyclohexanamineacetate yl)cyclohexyl)cyclopropanesulfonamide (Example #F.1.2)(R)-1-(Piperidin-3-yl)-6H- (R)-1-(1- N.1.9 1.51 (a) 347 pyrrolo[2,3-(Cyclopropylsulfonyl)piperidin- e][1,2,4]triazolo[4,3-3-yl)-6H-pyrrolo[2,3- a]pyrazine hydrochloride e][1,2,4]triazolo[4,3-(Example #I.1.1) a]pyrazine 1-(4-Methylpiperidin-3-yl)-1-(1-(Cyclopropylsulfonyl)-4- N.1.10 1.62 (a) 361 6H-pyrrolo[2,3-methylpiperidin-3-yl)-6H- e][1,2,4]triazolo[4,3- pyrrolo[2,3- a]pyrazine(Example #J.1.2) e][1,2,4]triazolo[4,3- a]pyrazinecis-3-(6H-Pyrrolo[2,3- N-(cis-3-(6H-Pyrrolo[2,3- N.1.11 1.43 (a) 333e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3- a]pyrazin-1- a]pyrazin-1-yl)cyclobutanamine (Example yl)cyclobutyl)cyclopropanesulfonamide#J.1.4) trans-3-(6H-Pyrrolo[2,3- N-(trans-3-(6H-Pyrrolo[2,3- N.1.12 1.25(a) 333 e][1,2,4]triazolo[4,3- e][1,2,4]triazolo[4,3- a]pyrazin-1-a]pyrazin-1- yl)cyclobutanamine yl)cyclobutyl)cyclopropanesulfonamidehydrochloride (Example #I.1.4) (R)-1-(Pyrrolidin-3-yl)-6H- (R)-1-(1-N.1.13 1.37 (a) 333 pyrrolo[2,3- (Cyclopropylsulfonyl)pyrrolidin-e][1,2,4]triazolo[4,3- 3-yl)-6H-pyrrolo[2,3- a]pyrazine hydrochloridee][1,2,4]triazolo[4,3- (Example #I.1.5) a]pyrazine((1R,3R)-3-(6H-Pyrrolo[2,3- N-(((1R,3R)-3-(6H- N.1.14 1.59 (a) 361e][1,2,4]triazolo[4,3- Pyrrolo[2,3- a]pyrazin-1- e][1,2,4]triazolo[4,3-yl)cyclopentyl)methanamine a]pyrazin-1- hydrochloride (Exampleyl)cyclopentyl)methyl)cyclopropanesulfonamide #F.1.1)(S)-1-(Pyrrolidin-3-yl)-6H- (S)-1-(1- N.1.15 1.49 (a) 333 pyrrolo[2,3-(Cyclopropylsulfonyl)pyrrolidin- e][1,2,4]triazolo[4,3-3-yl)-6H-pyrrolo[2,3- a]pyrazine hydrochloride e][1,2,4]triazolo[4,3-(Example #I.1.7) a]pyrazine (1S,3R,4R)-4-Ethyl-3-methyl-N-((1S,3R,4R)-4-Ethyl-3- N.1.16 1.68 (a) 389 3-(6H-pyrrolo[2,3-methyl-3-(6H- e][1,2,4]triazolo[4,3- pyrrolo[2,3- a]pyrazin-1-e][1,2,4]triazolo[4,3- yl)cyclopentanamine and a]pyrazin-1-(1R,3S,4S)-4-ethyl-3- yl)cyclopentyl)cyclopropanesulfonamidemethyl-3-(6H- and N- pyrrolo[2,3- ((1R,3S,4S)-4-ethyl-3-e][1,2,4]triazolo[4,3- methyl-3-(6H- a]pyrazin-1- pyrrolo[2,3-yl)cyclopentanamine e][1,2,4]triazolo[4,3- (prepared using A froma]pyrazin-1- Preparation #9 and yl)cyclopentyl)cyclopropanesulfonamidePreparation #12, HATU, and TEA, F with TEA) (R)-1-(1-Methylpiperazin-2-(R)-1-(4- N.1.17 1.55 (a) 362 yl)-6H-pyrrolo[2,3-(Cyclopropylsulfonyl)-1- e][1,2,4]triazolo[4,3-methylpiperazin-2-yl)-6H- a]pyrazine hydrochloride pyrrolo[2,3-(prepared using A from e][1,2,4]triazolo[4,3- Preparation #9 anda]pyrazine Preparation #16, HATU, TEA, C with TEA, H, I with 4 N HCl in1,4-dioxane) (S)-1-(Piperidin-3-yl)-6H- (S)-1-(1- N.1.18 1.57 (a) 347pyrrolo[2,3- (Cyclopropylsulfonyl)piperidin- e][1,2,4]triazolo[4,3-3-yl)-6H-pyrrolo[2,3- a]pyrazine (Example #I.1.3) e][1,2,4]triazolo[4,3-a]pyrazine

TABLE N.2 Examples prepared from(1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (Example #6, Step C) usingGeneral Procedure N R_(t) min Sulfonyl (Table 2, m/z ESI+ ChlorideProduct Ex. # Method) (M + H)⁺ CyclobutanesulfonylN-((1S,3R)-3-(6H-Pyrrolo[2,3- N.2.1 1.68 (a) 361 chloridee][1,2,4]triazolo[4,3-a]pyrazin-1- [Hande] yl)cyclopentyl)cyclo-butanesulfonamide Cyclopentanesulfonyl N-((1S,3R)-3-(6H-Pyrrolo[2,3-N.2.2 1.65 (a) 375 chloride e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclo- pentanesulfonamide 4-(Trifluoromethyl)benzene-N-((1S,3R)-3-(6H-Pyrrolo[2,3- N.2.3 1.95 (a) 451 1-sulfonyl chloridee][1,2,4]triazolo[4,3-a]pyrazin-1- [Lancaster] yl)cyclopentyl)-4-(trifluoromethyl)benzene- sulfonamide 3-(Trifluoromethyl)benzene-N-((1S,3R)-3-(6H-Pyrrolo[2,3- N.2.4 1.93 (a) 451 1-sulfonyl chloridee][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)-3-(trifluoromethyl)benzene- sulfonamide 4-ChlorobenzenesulfonylN-((1S,3R)-3-(6H-Pyrrolo[2,3- N.2.5 1.88 (a) 417 chloridee][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)-4-chloro-benzenesulfonamide 3-Chlorobenzenesulfonyl N-((1S,3R)-3-(6H-Pyrrolo[2,3-N.2.6 1.85 (a) 417 chloride e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-3-chloro- benzenesulfonamide BenzenesulfonylN-((1S,3R)-3-(6H-Pyrrolo[2,3- N.2.7 1.71 (a) 383 chloridee][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentyl)benzenesulfonamideCyclohexanesulfonyl N-((1S,3R)-3-(6H-Pyrrolo[2,3- N.2.8 1.28 (d) 389chloride e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclohexanesulfonamide 4-Cyanobenzene-N-((1S,3R)-3-(6H-Pyrrolo[2,3- N.2.9 1.78 (a) 408 1-sulfonyl chloridee][1,2,4]triazolo[4,3-a]pyrazin-1- [Maybridge] yl)cyclopentyl)-4-cyanobenzenesulfonamide 3-Cyanobenzene-1- N-((1S,3R)-3-(6H-Pyrrolo[2,3-N.2.10 1.74 (a) 408 sulfonyl chloride e][1,2,4]triazolo[4,3-a]pyrazin-1-[Maybridge] yl)cyclopentyl)-3- cyanobenzenesulfonamide3-Chloro-4-fluorobenzene- N-((1S,3R)-3-(6H-Pyrrolo[2,3- N.2.11 1.91 (a)435 1-sulfonyl chloride e][1,2,4]triazolo[4,3-a]pyrazin-1- [Lancaster]yl)cyclopentyl)-3-chloro-4- fluorobenzene-sulfonamide

TABLE N.3 Examples prepared from(S)-1-(piperidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazinehydrochloride (prepared using A from Preparation #3 and (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid, EDC•HCl, and TEA, C, H, andI) using General Procedure N R_(t) min Sulfonyl (Table 2, m/z ESI+Chloride Product Ex. # Method) (M + H)⁺ Propane-1- (S)-1-(1- N.3.1 1.61(a) 349 sulfonyl chloride (Propylsulfonyl)piperidin-3-yl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine Benzenesulfonyl(S)-1-(1- N.3.2 1.76 (a) 383 chloride (Phenylsulfonyl)piperidin-3-yl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine 4-Cyanobenzene-(S)-4-(3-(6H-Pyrrolo[2,3- N.3.3 1.78 (a) 408 1-sulfonyle][1,2,4]triazolo[4,3-a]pyrazin-1- chloride yl)piperidin-1-ylsulfonyl)benzonitrile Ethanesulfonyl(S)-1-(1-(Ethylsulfonyl)piperidin- N.3.4 1.49 (a) 335 chloride3-yl)-6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazine Methanesulfonyl(S)-1-(1- N.3.5 1.43 (a) 321 chloride (Methylsulfonyl)piperidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- a]pyrazine

TABLE N.4 Examples prepared fromcis-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanamine hydrochloride (Example #F.1.3) using GeneralProcedure N R_(t) min Sulfonyl (Table 2, m/z ESI+ Chloride Product Ex. #Method) (M + H)⁺ Cyclopropanesulfonyl N-(cis-3-(6H-Pyrrolo[2,3- N.4.11.45 (a) 361 chloride e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexyl)cyclopropanesulfonamide BenzenesulfonylN-(cis-3-(6H-Pyrrolo[2,3- N.4.2 1.68 (a) 397 chloridee][1,2,4]triazolo[4,3-a]pyrazin-1-yl) cyclohexyl)benzenesulfonamide4-Cyanobenzene- N-(cis-3-(6H-Pyrrolo[2,3- N.4.3 1.70 (a) 422 1-sulfonyle][1,2,4]triazolo[4,3-a]pyrazin-1- chloride yl)cyclohexyl)-4-cyanobenzenesulfonamide Ethanesulfonyl N-(cis-3-(6H-Pyrrolo[2,3- N.4.41.47 (a) 349 chloride e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclohexyl)ethanesulfonamide Propane-1- N-(cis-3-(6H-Pyrrolo[2,3- N.4.51.51 (a) 363 sulfonyl chloride e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexyl)propane-1- sulfonamide MethanesulfonylN-(cis-3-(6H-Pyrrolo[2,3- N.4.6 1.41 (a) 335 chloridee][1,2,4]triazolo[4,3-a]pyrazin-1-yl) cyclohexyl)methanesulfonamide

TABLE N.5 Examples prepared fromcis-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutanamine (Example #J.1.4) using General ProcedureN R_(t) min Sulfonyl (Table 2, m/z ESI+ Chloride Product Ex. # Method)(M + H)⁺ 4-Cyanobenzene- N-((1S,3S)-3-(6H- N.5.1 1.76 (a) 394 1-sulfonylPyrrolo[2,3- chloride e][1,2,4]triazolo[4,3- [Maybridge] a]pyrazin-1-yl)cyclobutyl)-4- cyano- benzenesulfonamideGeneral Procedure O: Displacement of an Aryl or Heteroaryl Halide withan Amine

To a microwave vessel is added an amine or an amine salt (preferably 1equiv), an aryl or heteroaryl halide (1-10 equiv, preferably 1.5 equiv),a solvent such as MeCN, n-PrOH, n-BuOH, toluene, DMSO, or EtOH(preferably EtOH), and a base such as K₂CO₃, Na₂CO₃, TEA or DIEA,preferably TEA or DIEA (1-5 equiv, preferably 2-4 equiv). The reactionmixture is subjected to microwave heating at about 100-200° C.(preferably about 130-150° C.) for about 0.5-8 h (preferably about 1-2h). In cases where the reaction did not proceed to completion asmonitored by TLC, LC/MS, or HPLC, the reaction may be resubjected to amicrowave at about 120-200° C. (preferably about 130-150° C.) for anadditional about 1-8 h (preferably about 1-2 h) with the optionaladdition of more aryl or heteroaryl halide (1-10 equiv, preferably 1.5equiv) and/or base such as K₂CO₃, Na₂CO₃, TEA or DIEA, preferably TEA orDIEA (1-5 equiv, preferably 2-4 equiv). This process is repeated untilthe reaction proceeds no further. After cooling to ambient temperature,the reaction is worked up using one of the following methods. Method 1:The reaction is concentrated under reduced pressure. Method 2: Areaction mixture containing a precipitate may be filtered to collect thetarget compound, while optionally washing with organic solvent orsolvents such as Et₂O, DCM and/or petroleum ether. Method 3: Thereaction mixture is diluted with an organic solvent such as MeOH, silicagel is added, and the mixture is concentrated under reduced pressure toprepare for separation by chromatography. Method 4: The reaction mixtureis concentrated under reduced pressure prior to the addition of anorganic solvent such as EtOAc or DCM and is then optionally washed withwater and/or brine, dried over anhydrous Na₂SO₄ or MgSO₄, filtered ordecanted, and concentrated under reduced pressure. Method 5: An organicsolvent such as EtOAc or DCM is added with the optional addition ofwater or brine and the layers are separated. The aqueous layer is thenoptionally extracted with additional organic solvent such as EtOAc orDCM. The combined organic layers are optionally washed with brine orwater, dried over anhydrous MgSO₄ or Na₂SO₄, filtered or decanted, andconcentrated under reduced pressure. In all cases, the crude material isoptionally purified by precipitation, crystallization, and/ortrituration from an appropriate solvent or solvents and/or bychromatography to give the target compound.

Illustration of General Procedure O

Example #O.1.16-((1S,3R)-3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)nicotinonitrile

To a microwave vessel was added(1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanaminehydrochloride (0.0979 g, 0.311 mmol, Example #6, Step C), EtOH (2 mL),6-chloronicotinonitrile (0.057 g, 0.41 mmol), and TEA (0.130 mL, 0.932mmol). The reaction mixture was heated in a CEM™ microwave at about 130°C. for about 1 h (250 psi maximum pressure, 5 min maximum ramp, 300maximum watts). After cooling to ambient temperature, the reaction wasconcentrated under reduced pressure and purified by silica gelchromatography eluting with DCM/MeOH/Et₂NH (970:27:3) to give6-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)nicotinonitrile(0.027 g, 25%): LC/MS (Table 2, Method a) R_(t)=1.24 min; MS m/z:345(M+H)⁺.

TABLE O.1 Examples prepared from(1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (Example #6, Step C) usingGeneral Procedure O R_(t) min Aryl or Heteroaryl (Table 2, m/z ESI+Halide Product Ex. # Method) (M + H)⁺ 6-Chloropyridazine-6-((1S,3R)-3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo- O.1.2 1.56 (a) 3463-carbonitrile (Ark [4,3-a]pyrazin-1-yl)cyclopentylamino)- Pharm)pyridazine-3- carbonitrile 4-Fluorobenzonitrile4-((1S,3R)-3-(6H-Pyrrolo[2,3- O.1.3 1.79 (a) 344e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)- benzonitrile2-Chloroquinazoline N-((1S,3R)-3-(6H-Pyrrolo[2,3- O.1.4 1.72 (a) 371e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)quinazolin- 2-amine2-Chloro-5- N-((1S,3R)-3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo- O.1.5 1.98(a) 388 (trifluoromethyl)pyridine [4,3-a]pyrazin-1-yl)cyclopentyl)-5-(trifluoromethyl)pyridin-2-amine 6-Chloro-5-6-((1S,3R)-3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo- O.1.6 1.88 (a) 363fluoronicotinonitrile [4,3-a]pyrazin-1-yl)cyclopentylamino)-5-fluoronicotinonitrile 6-Chloro-5-6-((1S,3R)-3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo- O.1.7 1.78 (a) 359methylnicotinonitrile [4,3-a]pyrazin-1-yl)cyclopentylamino)-5-methylnicotinonitrile

TABLE O.2 Examples prepared from(R)-1-(piperidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo [4,3-a]pyrazinehydrochoride (Example #I.1.1) and a heteroaryl halide using GeneralProcedure O R_(t) min Aryl or Heteroaryl (Table 2, m/z ESI+ HalideProduct Ex. # Method) (M + H)⁺ 6-Chloronicotinonitrile(R)-6-(3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo- O.2.1 1.76 (a) 345[4,3-a]pyrazin-1-yl)piperidin-1- yl)nicotinonitrile6-Chloropyridazine-3- (R)-6-(3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo- O.2.21.57 (a) 346 carbonitrile [Ark Pharm] [4,3-a]pyrazin-1-yl)piperidin-1-yl)pyridazine-3-carbonitrile 2-Chloro-5-(R)-1-(1-(5-(Trifluoromethyl)pyridin-2- O.2.3 2.04 (a) 388(trifluoromethyl)pyridine yl)piperidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

TABLE O.3 Examples prepared from(1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (Example #D.1.4) using GeneralProcedure O R_(t) min Aryl or Heteroaryl (Table 2, m/z ESI+ HalideProduct Ex. # Method) (M + H)⁺ 6- 6-((1R,3R)-3-(6H-Pyrrolo[2,3- O.3.11.65 (a) 345 Chloronicotinonitrile e][1,2,4] triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)nicotinonitrile 6-Chloropyridazine-6-((1R,3R)-3-(6H-Pyrrolo[2,3- O.3.2 1.53 (a) 346 3-carbonitrilee][1,2,4] triazolo[4,3-a]pyrazin-1- yl)cyclopentylamino)pyridazine-3-carbonitrile 4-Fluorobenzonitrile 4-((1R,3R)-3-(6H-Pyrrolo[2,3- O.3.31.81 (a) 344 e][1,2,4] triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)benzonitrile

TABLE O.4 Examples prepared fromcis-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanamine hydrochloride (Example #F.1.3) usingGeneral Procedure O R_(t) min Heteroaryl (Table 2, m/z ESI+ HalideProduct Ex. # Method) (M + H)⁺ 2-Chloro-5- N-(cis-3-(6H- O.4.1 1.66 (a)402 (trifluoro- Pyrrolo[2,3- methyl)- e][1,2,4]triazolo[4,3- pyridinea]pyrazin-1-yl) cyclohexyl)-5- (trifluoromethyl)- pyridin-2-amine

TABLE O.5 Examples prepared from4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine (prepared using A fromPreparation #9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid [Prime Organics], HATU, and TEA, C with TEA, and Iwith 4N HCl in 1,4-dioxane) and a heteroaryl halide using GeneralProcedure O Heteroaryl R_(t) min m/z ESI+ halide Product Ex. # (method)(M + H)⁺ 6-Fluoro- 6-(4-(6H-Pyrrolo[2,3- O.5.1 1.48 (a) 385nicotinonitrile e][1,2,4]triazolo[4,3- [Matrix] a]pyrazin-1-yl)bicyclo[2.2.2]octan- 1-ylamino)nicotinonitrile

TABLE O.6 Example prepared from (1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride(prepared using C from Preparation #A.1 with TEA, I with 4 N HCl in1,4-dioxane) using General Procedure O Aryl or R_(t) min Heteroaryl(Table 2, m/z ESI+ halide Product Ex. # Method) (M + H)⁺ 6-Fluoro-4-6-((1S,3R)-3-(6H- O.6.1 1.81 (a) 359 methyl- Pyrrolo[2,3-nicotinonitrile yl)e][1,2,4]triazolo[4,3- (prepared a]pyrazin-1- usingHH cyclopentylamino)-4- from methylnicotinonitrile Preparation #23)

TABLE O.7 Example prepared from (1R,4S)-3,3-Dimethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride and(1S,4R)-3,3-dimethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride(prepared using prepared using EE from Preparation #25 andN,N-dibenzylamine, Y with MeOH, FF, P, GG with LiOH, A from Preparation#9 with HATU and TEA, C with TEA, H, I with 4 N HCl in 1,4-dioxane)using General Procedure O Aryl or R_(t) min Heteroaryl (Table 2, m/zESI+ Halide Product  Ex. # Method) (M + H)⁺ 5-Chloro-(1R,4S)-3,3-Dimethyl-4- O.7.1 0.92 (d) 271 pyrazine-2- (6H-pyrrolo[2,3-carbonitrile e][1,2,4]triazolo[4,3- 1-yl)a]pyrazin- cyclopentanamine and(1S,4R)-3,3-dimethyl-4- (6H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1- yl)cyclopentanamine

TABLE O.8 Example prepared from (R)-1-(1-methylpiperazin-2-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine hydrochloride (preparedusing A from Preparation #9 and Preparation #16, C, H, I) using GeneralProcedure O R_(t) min Heteroaryl (Table 2, m/z ESI+ Halide Product Ex. #Method) (M + H)⁺ 6-Chloro- (R)-6-(4-Methyl-3-(6H- O.8.1 1.70 (a) 360nicotinonitrile pyrrolo[2,3- e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperazin- 1-yl)nicotinonitrileGeneral Procedure O.1

Displacement of an Aryl or Heteroaryl Halide with an Amine (UnderThermal Conditions)

A round bottom flask is charged with a mixture of an amine or an aminesalt (preferably 1 equiv), an aryl or heteroaryl halide (1-10 equiv,preferably 1.5 equiv), a solvent such as MeCN, toluene, DMSO, EtOH, orDMF (preferably DMF), and a base such as K₂CO₃, Na₂CO₃, TEA or DIEA,preferably TEA or K₂CO₃ (1-5 equiv, preferably 2-4 equiv). The reactionmixture is heated at about 40-220° C. (preferably about 65° C.) forabout 0.5-16 h (preferably about 8.5 h). In cases where the reaction didnot proceed to completion as monitored by TLC, LC/MS, or HPLC, thereaction may be resubjected heating at about 40-220° C. (preferablyabout 65° C.) for an additional about 1-12 h (preferably about 1-2 h)with the optional addition of more aryl or heteroaryl halide (1-10equiv, preferably 1.5 equiv) and/or base such as K₂CO₃, Na₂CO₃, TEA orDIEA, preferably TEA or K₂CO₃ (1-5 equiv, preferably 2-4 equiv). Thisprocess is repeated until the reaction proceeds no further. Aftercooling to ambient temperature, the reaction mixture is subjected to oneof the following methods. Method 1: The reaction is concentrated todryness under reduced pressure. Method 2: A reaction mixture containinga precipitate may be filtered to collect the target compound, whileoptionally washing with organic solvent or solvents such as Et₂O, DCMand/or petroleum ether. Method 3: The reaction mixture is diluted withan organic solvent (such as MeOH) silica gel is added, and the mixtureis concentrated under reduced pressure to prepare for separation bychromatography. Method 4: The reaction mixture is concentrated underreduced pressure prior to the addition of an organic solvent such asEtOAc or DCM and is then optionally washed with water and/or brine,dried over anhydrous Na₂SO₄ or MgSO₄, filtered or decanted, andconcentrated under reduced pressure. Method 5: An organic solvent suchas EtOAc or DCM is added with the optional addition of water or brineand the layers are separated. The aqueous layer is then optionallyextracted with additional organic solvent such as EtOAc or DCM. Thecombined organic layers are optionally washed with brine or water, driedover anhydrous MgSO₄ or Na₂SO₄, filtered or decanted, and concentratedunder reduced pressure. In all cases, the crude material is optionallypurified by precipitation, crystallization, and/or trituration from anappropriate solvent or solvents and/or by chromatography to give thetarget compound.

Illustration of General Procedure O.1

Preparation #O.1.1:N-(4-(6-Tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)benzo[d]oxazol-2-amine

A pear shaped flask was charged with4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine(0.20 g, 0.46 mmol, Example #7, Step B) and 2-chlorobenzo[d]oxazole(0.18 g, 1.1 mmol, TCI) in DMF (5.0 mL). To the suspension was addedK₂CO₃ (0.16 g, 1.1 mmol) and the mixture was heated to about 65° C. forabout 8.5 h. The mixture was cooled to room temperature and the solventwas removed under reduced pressure. The residue was dissolved into EtOAc(25 mL) and washed with water and brine (25 mL each). The organicsolution was dried over anhydrous MgSO₄, filtered, and concentrated todryness under reduced pressure to giveN-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)benzo[d]oxazol-2-amine(0.26 g, 95%, 95% purity by ELSD): LC/MS (Table 2, Method d) R_(t)=1.48min; MS m/z: 554 (M+H)⁺.

General Procedure P: Boc-Protection of an Amine

To a solution of an amine (preferably 1 equiv) in an organic solvent(for example MeCN, 1,4-dioxane or THF, preferably THF) is optionallyadded an aqueous base such as Na₂CO₃, NaOH, K₂CO₃ or NaHCO₃ (2-20 equiv,preferably 10 equiv of Na₂CO₃) or an organic base such as TEA or DIEA(1-5 equiv, preferably 1-2 equiv) followed by addition of di-tert-butyldicarbonate (1-1.5 equiv, preferably 1.2 equiv). The reaction is stirredat about 10-40° C. (preferably ambient temperature) for about 2-24 h(preferably about 2-6 h) and worked up using one of the followingmethods. Method 1: An organic solvent (such as Et₂O, EtOAc or DCM) andwater are added and the layers are separated. The aqueous layer isextracted with additional organic solvent and the combined organiclayers may be optionally washed with brine, dried over anhydrous Na₂SO₄or MgSO₄, and then decanted or filtered prior to concentrating underreduced pressure. Method 2: The reaction mixture is partitioned betweenan organic solvent (such as Et₂O, EtOAc or DCM) and aqueous acid (suchas HCl). The acidic layer is extracted with additional organic solventand the combined organic layers may be optionally washed with brine. Theorganic layer is optionally dried over anhydrous Na₂SO₄ or MgSO₄, andthen decanted or filtered prior to concentrating under reduced pressure.Method 3: An organic solvent (such as Et₂O, EtOAc or DCM) and water areadded and the layers are separated. The aqueous layer is acidified usingan acid (such as AcOH) which forms a precipitate, which can then bedecanted or filtered with optionally washing with excess water. Thecrude material is optionally purified by precipitation, crystallization,and/or trituration from an appropriate solvent or solvents and/or bychromatography to give the target compound.

Illustration of General Procedure P

Preparation #P.1(1R,3S)-3-((tert-Butoxycarbonylamino)methyl)cyclopentanecarboxylic acid

To a solution of (1R,3S)-3-(aminomethyl)cyclopentanecarboxylic acid(0.500 g, 3.49 mmol, AFID) in THF (4 mL) and water (4 mL) was addedNa₂CO₃ (1.11 g, 10.5 mmol) and di-tert-butyl dicarbonate (0.915 g, 4.19mmol). The reaction was stirred at ambient temperature for about 4 h.EtOAc (15 mL) and aqueous HCl (1N, 15 mL) were added and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×10 mL) and thecombined organic layers were washed with brine (10 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure to give (1R,3S)-3-((tert-btoxycarbonylamino)methyl)cyclopentanecarboxylic acid (0.300 g, 35%yield). ¹H NMR (DMSO-d₆) δ 11.97 (s, 1H), 6.83 (s, 1H), 2.87 (t, J=6.4,2H), 2.73-2.58 (m, 1H), 2.04-1.87 (m, 2H), 1.82-1.68 (m, 2H), 1.68-1.58(m, 1H), 1.37 (s, 9H), 1.34-1.19 (m, 2H).

General Procedure Q: Cbz-Protection of an Amine

To a solution of an amine (preferably 1 equiv) and a base (for example,Na₂CO₃, 1-3 equiv, preferably 3 equiv) in water or aqueous organicsolvent (for example, water/MeCN) is added a solution of benzyl2,5-dioxopyrrolidin-1-yl carbonate (1-2 equiv, preferably 1.3 equiv) inan organic solvent such as MeCN. The reaction is stirred at ambienttemperature for about 8-24 h (preferably about 16 h) and thenconcentrated under reduced pressure. The resulting aqueous solution isacidified by adding an acid such as aqueous NH₄Cl or HCl and is thenextracted with an organic solvent (such as EtOAc or DCM). The combinedorganic extracts are optionally washed with water and/or brine, driedover anhydrous Na₂SO₄ or MgSO₄, filtered or decanted, and concentratedunder reduced pressure. The crude material is optionally furtherpurified by precipitation, crystallization, and/or trituration from anappropriate solvent or solvents and/or by chromatography to give thetarget compound.

Illustration of General Procedure Q

Preparation #Q.1 1-(Benzyloxycarbonyl)piperidine-4-carboxylic acid

To a solution of piperidine-4-carboxylic acid (10.0 g, 77.4 mmol) andNa₂CO₃ (8.21 g, 77.4 mmol) in water (100 mL) was added a solution ofbenzyl 2,5-dioxopyrrolidin-1-yl carbonate (19.3 g, 77.4 mmol) in MeCN(100 mL). The reaction was stirred at ambient temperature for about 16 hand then concentrated under reduced pressure. The resulting aqueoussolution was quenched with aqueous NH₄Cl and was then extracted withEtOAc (2×100 mL). The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure togive 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid as a white solid(4.56 g, 22%): LC/MS (Table 2, Method a) R_(t)=1.93 min; MS m/z: 262(M−H)⁻.

General Procedure R: Reduction of a Pyridine

A substituted pyridine (preferably 1 equiv) and platinum(IV) oxide(0.05-0.20 equiv, preferably 0.09 equiv) in AcOH are shaken underhydrogen at about 15-90 psi (preferably about 60 psi) for about 1-10days (preferably about 3-5 days). The reaction is filtered throughCelite® then concentrated under reduced pressure and optionally furtherpurified by precipitation, crystallization, and/or trituration from anappropriate solvent or solvents and/or by chromatography to give thetarget compound.

Illustration of General Procedure R

Preparation #R.1 4-Methylpiperidine-3-carboxylic Acid Acetate

4-Methylnicotinic acid (2.00 g, 14.6 mmol) and platinum(IV) oxide (0.30g, 1.3 mmol) in AcOH (70 mL) were shaken under hydrogen at about 60 psifor about 3 days. The reaction was filtered through Celite® thenconcentrated under reduced pressure to afford4-methylpiperidine-3-carboxylic acid acetate as an oil (2.9 g, 98%):LC/MS (Table 2, Method a) R_(t)=0.55 min; MS m/z: 144 (M+H)⁺.

General Procedure S: Reduction of an Ester to an Alcohol

A reducing agent (2.0-2.5 equiv, preferably 2.1 equiv), such as asolution of DIBAL-H, is added drop-wise to a solution of an ester(preferably 1 equiv) in an organic solvent (such as THF or Et₂O,preferably THF) at about 0-25° C. (preferably about 0° C.). The reactionis stirred for about 1-3 h (preferably about 1 h) before quenching with10% aqueous potassium sodium tartrate solution in water. The reaction isallowed to stir for about 1 h before it is concentrated under reducedpressure. The residue is partitioned with an organic solvent (such asEtOAc or DCM, preferably EtOAc) and then is washed with brine. Theorganic layer is dried over anhydrous Na₂SO₄ or MgSO₄, filtered, andconcentrated to constant weight. The crude material is optionallyfurther purified by precipitation, crystallization, and/or triturationfrom an appropriate solvent or solvents and/or by chromatography to givethe target compound.

Illustration of General Procedure S

Preparation #S.1 tert-Butyl3-(hydroxymethyl)-4-methylpiperidine-1-carboxylate

DIBAL-H (1 M in toluene, 27.3 mL, 27.3 mmol) was added drop-wise to asolution of 1-tert-butyl 3-methyl 4-methylpiperidine-1,3-dicarboxylate(3.35 g, 13.02 mmol, prepared using R from Preparation #Y.1 and P) inTHF (40 mL) at about 0° C. The reaction mixture was stirred for about 1h before quenching with 10% aqueous potassium sodium tartrate solutionin water (50 mL). The reaction mixture was allowed to stir for about 1 hbefore it was concentrated under reduced pressure. The residue waspartitioned with EtOAc (200 mL) and brine (3×100 mL). The organic layerwas dried over anhydrous Na₂SO₄, filtered, and concentrated to constantweight to afford tert-butyl3-(hydroxymethyl)-4-methylpiperidine-1-carboxylate as a clear oil (2.58g, 86%): LC/MS (Table 2, Method a) R_(t)=2.10 min; MS m/z: 230 (M+H)⁺.

General Procedure T: Oxidation of an Alcohol to an Aldehyde

To a solution of an alcohol (preferably 1 equiv) in DCM is addedDess-Martin periodinane (1.0-1.5 equiv, preferably 1.2 equiv). Thereaction is stirred at ambient temperature for about 4-24 h (preferablyabout 8-16 h). The reaction is partitioned between an organic solventsuch as EtOAc or DCM (preferably EtOAc) and an aqueous base such assaturated aqueous NaHCO₃ or Na₂CO₃ (preferably Na₂CO₃). The organiclayer is separated, filtered through Celite®, and washed with an aqueousbase such as saturated aqueous NaHCO₃ or Na₂CO₃ (preferably Na₂CO₃). Theorganic layer is dried over anhydrous Na₂SO₄ or MgSO₄, filtered, andconcentrated under reduced pressure to a constant weight. The crudematerial is optionally purified by precipitation, crystallization,and/or trituration from an appropriate solvent or solvents and/or bychromatography to give the target compound.

Illustration of General Procedure T

Preparation #T.1 tert-Butyl 3-formyl-4-methylpiperidine-1-carboxylate

To a solution of tert-butyl3-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (2.58 g, 11.2 mmol,Preparation #S.1) in DCM (50 mL) was added Dess-Martin periodinane (5.73g, 13.5 mmol). The reaction was stirred at ambient temperature for about16 h before it was partitioned between EtOAc (150 mL) and saturatedaqueous NaHCO₃ (150 mL). The organic layer was filtered through Celite®then washed with saturated aqueous Na₂CO₃ (2×150 mL). The organic layerwas separated and dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to a constant weight to affordtert-butyl 3-formyl-4-methylpiperidine-1-carboxylate as a clear oil(1.49 g, 58%): LC/MS (Table 2, Method a) R_(t)=2.39 min; MS m/z: 228(M+H)⁺.

General Procedure U: Formation of a Semicarbazide

To a flask containing a hydrazine (preferably 1 equiv) in an organicsolvent (such as CHCl₃, THF, or DCM, preferably CHCl₃) is added anorganic base (1-3 equiv, preferably 1 equiv) such as TEA, DIEA, NMM, orpyridine (preferably TEA). The reaction mixture is optionally cooled toabout −10 to 10° C. (preferably about 0° C.) and a carbamoyl chloride(neat or as a solution in a suitable organic solvent as listed above,preferably as a solution in a suitable organic solvent) (1-2 equiv,preferably 1.2 equiv) is added. The reaction mixture is stirred at about0-60° C. (preferably about 45° C.) for about 1-24 h (preferably about 16h). A suitable organic solvent (such as EtOAc or DCM) is added and thesolution is washed with water and brine. The layers are partitioned andthe organic solution is dried over anhydrous Na₂SO₄ or MgSO₄, filtered,and concentrated to dryness under reduced pressure to give the targetcompound. The crude material is optionally further purified byprecipitation, crystallization, or trituration from an appropriatesolvent or solvents or by chromatography to give the target compound.

Illustration of General Procedure U

Preparation #U.1N′-(5-Tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)piperidine-1-carbohydrazide

A 25 mL round-bottomed flask was charged with2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.075 g, 0.25 mmol,Preparation #9) and TEA (0.041 mL, 0.29 mmol) in CHCl₃ (1.2 mL) to givea brown suspension. Piperidine-1-carbonyl chloride (0.040 g, 0.27 mmol)was added and the reaction was stirred at ambient temperature for about3 h. The reaction mixture was heated to about 45° C. for about 16 h. Themixture was cooled to ambient temperature, DCM (25 mL) was added, andthe solution was washed with water and brine (about 5 mL each). Thelayers were separated and the organic solution was dried over anhydrousMgSO₄, filtered, and concentrated to dryness under reduced pressure togiveN′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)piperidine-1-carbohydrazide(0.11 g, 100%): LC/MS (Table 2, Method a) R_(t)=2.09 min; MS m/z: 415(M+H)⁺.

General Procedure V: Cyclization of a Semicarbazide

To a flask containing a semicarbazide (preferably 1 equiv) is addedPOCl₃ (10-100 equiv, preferably 50 equiv). The reaction mixture isstirred at about 25-120° C. (preferably about 70-100° C.) for about 1-10h (preferably about 2-4 h). Optionally, the reaction mixture is stirredat ambient temperature for about 1-48 h (preferably about 24-36 h). Ifthe mixture had been heated at an elevated temperature, it is cooled toambient temperature before pouring over ice or ice water. A suitableorganic solvent (such as EtOAc or DCM) and an aqueous base (such asNa₂CO₃, NaHCO₃, or NaOH) are added to the mixture and the organic layeris separated. Optionally, the aqueous solution is further extracted witha suitable organic solvent (such as EtOAc or DCM). The combined organicextracts are dried over anhydrous Na₂SO₄ or MgSO₄, filtered, andconcentrated to dryness under reduced pressure to give the targetcompound. The crude material is optionally purified by precipitation,crystallization, or trituration from an appropriate solvent or solventsor by chromatography to give the target compound.

Illustration of General Procedure V

Preparation #V.1:1-(Piperidin-1-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

A flask was charged withNV-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)piperidine-1-carbohydrazide(0.18 g, 0.43 mmol, Preparation #U. 1) followed by the addition of POCl₃(2.0 mL, 21.5 mmol). The mixture was heated to about 100° C. for about 2h. The reaction mixture was cooled to ambient temperature and stirredfor about 36 h at ambient temperature. The mixture was slowly pouredover ice (about 15 g), followed by the addition of DCM (50 mL) and asolution of saturated aqueous Na₂CO₃ (25 mL) to the resultingsuspension. The layers were separated and the organic solution was driedover anhydrous MgSO₄, filtered, and concentrated to dryness underreduced pressure to give1-(piperidin-1-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.11 g, 63%) as a brown solid: LC/MS (Table 2, Method a) R_(t)=2.36min; MS m/z: 397 (M+H)⁻.

General Procedure W: Formation of an Acid Chloride

To a solution of a carboxylic acid (preferably 1 equiv) in an organicsolvent (preferably DCM) is added oxalyl chloride (1.2-2.0 equiv,preferably 2 equiv) followed by DMF (0.01-0.10 equiv, preferably about0.05 equiv). The reaction is stirred at about 0-40° C. (preferablyambient temperature) for about 3-6 h (preferably about 4 h) before it isconcentrated under reduced pressure to a constant weight to give thetarget compound.

Illustration of General Procedure W

Preparation #W.1: 2-Methylcyclohexanecarbonyl chloride

To a solution of 2-methylcyclohexanecarboxylic acid (6.00 mL, 42.6 mmol,mixture of cis and trans) in DCM (60 mL) was added oxalyl chloride (4.80mL, 55.3 mmol) followed by DMF (0.03 mL, 0.4 mmol). The reaction wasstirred at ambient temperature for about 4 h before it was concentratedunder reduced pressure to a constant weight to afford2-methylcyclohexanecarbonyl chloride (mixture of diastereomers) as ayellow oil (7.0 g, 97%): ¹H NMR (400 MHz, CDCl₃) δ 2.98-2.94 (m, 1H),2.39-2.35 (m, 1H), 1.91-1.82 (m, 1H), 1.79-1.72 (m, 1H), 1.69-1.60 (m,2H), 1.57-1.47 (m, 2H), 1.42-1.36 (m, 1H), 1.34-1.26 (m, 1H), 1.04-0.96(m, 3H).

General Procedure X: Formation of a Urea Using CDI

To a flask containing an amine or an amine salt (preferably 1 equiv) isadded CDI (1-2 equiv, preferably 1.10 equiv) and an organic solvent(such as 1,4-dioxane, THF, DCM, DMF, or pyridine, preferably pyridine).If an amine salt is used, pyridine is used as the solvent. The reactionmixture is stirred at ambient temperature for about 2-24 h (preferablyabout 16 h). A second amine (1-3 equiv, preferably 1.10 equiv) is thenadded to the mixture which is stirred at ambient temperature for about2-24 h (preferably about 16 h). The organic solvent is optionallyremoved under reduced pressure. The crude material can be partitionedbetween an organic solvent (such as EtOAc or DCM) and water, an aqueousbase (such as saturated aqueous NaHCO₃) or brine. The layers areseparated and the organic solution is optionally washed with water, anaqueous base (such as saturated aqueous NaHCO₃) and/or brine, dried overanhydrous Na₂SO₄ or MgSO₄, filtered, and concentrated under reducedpressure to give the target compound. The crude material is optionallypurified by precipitation, crystallization, or trituration from anappropriate solvent or solvents or by chromatography to give the targetcompound.

Illustration of General Procedure X

Example #X.1.1N-(cis-3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexyl)pyrrolidine-1-carboxamide

To a flask containingcis-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanaminehydrochloride (0.050 g, 0.171 mmol, Example #F.1.3) was added CDI (0.030g, 0.188 mmol) and pyridine (2 mL). The reaction mixture was stirred atambient temperature for about 16 h. Pyrrolidine (0.016 mL, 0.188 mmol)was added to the reaction mixture and stirred for about 16 h. Thesolvent was removed under reduced pressure and the crude material waspurified by RP-HPLC (Table 2, Method j). The appropriate fractions werecombined, the solvent was mostly removed under reduced pressure, and thesolid was filtered and dried under lyophilization to giveN-(cis-3-(6H-pyrrolo[2,3-e][1, 2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexyl)pyrrolidine-1-carboxamide(0.010 g, 16%): LC/MS (Table 2, Method a) R_(t)=1.45 min; MS m/z 354(M+H)⁺.

General Procedure Y: Formation of an Ester from a Carboxylic Acid

A solution of a carboxylic acid (preferably 1 equiv) and a mineral acid(such as H₂SO₄ or HCl, preferably 0.2-3 equiv of H₂SO₄, preferably asaturated solution of HCl in an alcohol (such as MeOH or EtOH,preferably MeOH) is stirred at about 0-80° C. (preferably about 60° C.when using H₂SO₄ or preferably ambient temperature when using HCl) forabout 8-24 h (preferably about 16 h). The reaction is concentrated underreduced pressure and then is partitioned with EtOAc or DCM (preferablyEtOAc) and saturated aqueous NaHCO₃. The organic layer is dried overanhydrous Na₂SO₄ or MgSO₄, filtered, and concentrated under reducedpressure to a constant weight. The crude material is optionally purifiedby precipitation, crystallization, and/or trituration from anappropriate solvent or solvents and/or by chromatography to give thetarget compound.

Illustration of General Procedure Y

Preparation #Y.1 Methyl 4-methylnicotinate

A solution of 4-methylnicotinic acid (2.00 g, 14.6 mmol) andconcentrated H₂SO₄ (4.66 mL, 87.6 mmol) in MeOH (50 mL) was heated atabout 60° C. for about 16 h. The reaction was concentrated under reducedpressure then partitioned with EtOAc (150 mL) and saturated aqueousNaHCO₃ (200 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure to a constant weightto afford methyl 4-methylnicotinate as a clear liquid (2.30 g, 94%):LC/MS (Table 2, Method a) R_(t)=1.67 min; MS m/z: 152 (M+H)⁺.

General Procedure Z: N-Alkylation Using an Alkyl Halide or α-Haloketone

A round bottom flask is charged with a base (such as NaH, 60% dispersionin mineral oil), K₂CO₃, or Cs₂CO₃, preferably NaH, (60% dispersion inmineral oil), 1-1.5 equiv, preferably 1.2 equiv) and an organic solvent(such as DMF or NMP, preferably DMF). The mixture is cooled to about−10-10° C. (preferably about 0° C.) and a solution of an appropriatelysubstituted amine (preferably 1 equiv) in an organic solvent (such asDMF) is added. The reaction mixture is stirred for about 5-90 min(preferably about 15 min) at about −10° C.-ambient temperature(preferably about 0° C.) followed by the addition of an alkyl halide orα-haloketone (1-2 equiv, preferably 1.5 equiv). The reaction mixture isstirred at about −10° C.-ambient temperature (preferably about 0° C.)for about 0.5-2 h (preferably about 0.5 h), and is then warmed to roomtemperature (in cases where the mixture had been cooled throughout thereaction duration). The reaction mixture is stirred at room temperaturefor about 1-20 h (preferably about 2 h). The organic solvent is removedunder reduced pressure and the mixture can be purified by one of thefollowing methods. Method 1) The mixture may be diluted with water andan organic solvent (for example, EtOAc or DCM). The layers are separatedand the aqueous is extracted with organic solvent (such as EtOAc and/orDCM). The combined organic layers are optionally washed with brine,dried over anhydrous MgSO₄, filtered, and concentrated to dryness underreduced pressure. Method 2) The crude material is optionally purified byprecipitation, crystallization, and/or trituration from an appropriatesolvent or solvents and/or by chromatography to give the targetcompound.

Illustration of General Procedure Z

Preparation #Z.1N-Methyl-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide

A round bottom flask was charged with sodium hydride (60% dispersion inmineral oil, 0.013 g, 0.33 mmol) and DMF (1 mL) to give a whitesuspension. The suspension was cooled to about 0° C. followed by theaddition of a solution ofN-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide(0.15 g, 0.27 mmol, Example #7, Step C) in DMF (2 mL). The reactionmixture was stirred for about 15 min and iodomethane (0.06 g, 0.41 mmol)was added. The reaction mixture was stirred at about 0° C. for about 30min, warmed to room temperature, and stirring was continued for about 2h. The solvent was removed under reduced pressure. The residue wasdissolved in DCM (5 mL) then purified by flash silica gel chromatographyusing EtOAc as the eluant to giveN-methyl-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1, 2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide(0.068 g, 45%) as a yellow solid: LC/MS (Table 1, Method a) R_(t)=2.35min; LC/MS m/z 555 (M+H)⁺.

General Procedure AA: Cyclization of an Amide Using aDithiadiphosphetane Reagent

To a solution of an amide (preferably 1 equiv) in an organic solvent(preferably 1,4-dioxane) is added a thiolating reagent such asLawesson's reagent or Belleau's reagent(2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)(preferably Lawesson's reagent) (0.5-2.0 equiv, preferably 0.6 equiv).The reaction is heated at about 25-120° C. (preferably about 80° C.) forabout 0.5-10 h (preferably about 1 h). The reaction mixture is allowedto cool to ambient temperature and a Lewis acid, such asdiacetoxymercury, mercury dichloride, silver nitrate, copper bromide(preferably diacetoxymercury) (1-3 equiv, preferably 1 equiv) is added.The reaction mixture is stirred at about 20-60° C. (preferably ambienttemperature) for about 0.5-4 h (preferably about 1 h). Optionally,additional Lewis acid (preferably diacetoxymercury) (0.2-1.0 equiv,preferably 0.5 equiv) is added and the reaction is continued for about10 min-3 h (preferably about 15 min). The reaction mixture is added toan organic solvent (preferably EtOAc) and filtered, preferably through apad of Celite®. The filtrate is concentrated under reduced pressure togive the target compound. Optionally, the product can be purified bycrystallization or trituration from an appropriate solvent or solvents,or by chromatography to give the target compound.

Illustration of General Procedure AA

Preparation #AA.1: tert-Butyl4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate(44 g, 83 mmol, Example #13, Step H) in 1,4-dioxane (500 mL) was addedLawesson's reagent (20.2 g, 50.0 mmol). The reaction was heated at about80° C. for about 1 h. The reaction was allowed to cool to ambienttemperature followed by the addition of diacetoxymercury (26.6 g, 83.0mmol). After about 1 h, additional diacetoxymercury (13.3 g, 42.0 mmol)was added. After about 15 min, the reaction was poured into stirredEtOAc (2 L). After about 15 min the reaction was filtered throughCelite® and the filtrate was concentrated under reduced pressure. Theresulting residue was triturated with EtOAc (500 mL) and filtered. Thefiltrate was concentrated under reduced pressure and purified by silicagel chromatography (330 g column) eluting with a gradient of 10-50%EtOAc in heptane to provide tert-butyl4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(19 g, 44%) as a white solid: LC/MS (Table 2, Method a) R_(t)=2.57 min;MS m/z: 510 (M+H)⁺.

General Procedure BB: Knoevenagel Condensation to Form a SubstitutedCyclopentadiene

A round-bottom flask is charged with an organic solvent (for example THFor diethylene glycol dimethyl ether; preferably THF), followed by theportion-wise addition of sodium hydride (60% dispersion in mineral oil)(preferably 1 equiv). An organic solvent can optionally be added. Thereaction mixture is cooled to about −10° C. to 0° C. (preferably about0° C.). A β-keto ester (preferably 1 equiv) is added drop-wise at a rateto keep the internal temperature below about 10° C. The resultingmixture is stirred at about 0-25° C. (preferably about 25° C.) for about0.5-2 h (preferably about 0.5 h), followed by drop-wise addition of anα-halo ketone (preferably 0.45-0.55 equiv). The resulting mixture isheated to about 40-80° C. (preferably about 50° C.) for about 3-24 h(preferably about 19 h). The organic solvent is removed under reducedpressure and the resulting crude material is treated with water andplaced in an ice bath. The resulting suspension is filtered after about1-3 h (preferably about 2 h) and the filter cake is washed with waterand dried under vacuum for about 1-3 h (preferably about 1 h). Theresulting solid is suspended in an organic solvent (preferably Et₂O) andis collected by vacuum filtration, washed with an organic solvent(preferably Et₂O), and dried under vacuum to give the desired product asa sodium salt of the enolate.

Illustration of General Procedure BB

Preparation #BB.1: Sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate

A round bottom flask was charged with THF (1.5 L) followed by theportion-wise addition of sodium hydride (60% dispersion in mineral oil,70.0 g, 1.75 mol). Additional THF (500 mL) was added and the resultingmixture was cooled to about −10° and ethyl propionylacetate (250 mL,1.80 mol) was added drop-wise over about 1 h in order to keep internaltemperature below about 10° C. The resulting mixture was stirred atambient temperature for about 0.5 h to give a clear yellow solution, andmethyl 4-chloroacetoacetate (100 mL, 0.88 mol) was added drop-wise overabout 5 min. The resulting mixture was heated at about 50° C. for about19 h to give a reddish orange suspension. The reaction mixture wascooled to ambient temperature, concentrated under reduced pressure andthe resulting liquid was transferred to a beaker and diluted with water(350 mL). The mixture was stirred and placed in an ice bath for about 2h. The solid was collected by vacuum filtration and the filter cake wasrinsed with water (150 mL) and dried under vacuum for about 1 h. Thesolid was suspended in Et₂O (1.5 L), filtered, washed with Et₂O (1.5 L),and dried under vacuum. The resulting solid was azeotroped with toluene(1 L) to give a solid that was resuspended in Et₂O (1 L) and collectedby vacuum filtration. The filter cake was washed with Et₂O (500 mL) anddried under vacuum to give sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(204.2 g, 89%) as beige solid: ¹H NMR (DMSO-d₆) δ 3.94 (q, J=7.1 Hz,2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66 (s, 2H), 1.13 (t, J=7.1Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).

General Procedure CC: Decarboxylation of a β-Ketoester Enolate

A round-bottom flask is charged with an appropriate β-keto ester or itssodium enolate (preferably 1 equiv), an organic solvent (for examplediethylene glycol dimethyl ether), and AcOH (2-5 equiv, preferably 2.5equiv). To the resulting mixture is added sodium iodide (2-5 equiv,preferably 3.5 equiv) portion-wise. The reaction is heated to reflux forabout 1-5 h (preferably about 3 h). The reaction is cooled to ambienttemperature and is poured into a mixture of ice and saturated sodiumbicarbonate solution. The resulting mixture is extracted with an organicsolvent (preferably Et₂O). The combined organic layers are dried overanhydrous Na₂SO₄ or MgSO₄, filtered, and concentrated to dryness underreduced pressure. The crude material is optionally purified by vacuumdistillation, precipitation, crystallization, and/or trituration from anappropriate solvent or solvents and/or by chromatography to give thetarget compound.

Illustration of General Procedure CC

Preparation #CC.1: Ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate

A round-bottom flask was charged with sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(250 g, 0.94 mol, Preparation #BB.1) and diglyme (1.1 L) to give a greensuspension, followed by AcOH (140 mL, 2.4 mol). To the resulting mixturewas added sodium iodide (490 g, 3.3 mol) portion-wise over about 5-10min. Upon addition, the temperature rose from about 16° C. to about 36°C. The reaction mixture was then heated to reflux for about 3 h, cooledto room temperature, and poured over a mixture of ice (2 L) andsaturated aqueous NaHCO₃ (4 L). The resulting material was extractedwith Et₂O (4×1.2 L) and the combined organic layers were dried overanhydrous MgSO₄ and filtered. The solvent was removed under reducedpressure to give a brown liquid (250 mL) that was purified by vacuumdistillation (80-92° C., 0.3 Torr) to give ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate (95.7 g, 56%) as a yellow syrup:¹H NMR (CDCl₃) δ 6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69 (m, 1H),2.75-2.57 (m, 2H), 2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H), 1.23-1.18 (m,3H).

General Procedure DD: Hydrogenation of an Alkene

A round-bottom flask is charged with 10% palladium on carbon (about0.02-0.05 equiv, preferably 0.02 equiv). The flask is evacuated thenflushed with nitrogen 2-5 times (preferably 3 times), then is optionallycooled to about −10-10° C. (preferably about 0° C.) prior to addition ofan organic solvent (preferably EtOAc) under a nitrogen atmosphere. Thecooling bath is removed and to the mixture is added an alkene(preferably 1 equiv) neat or optionally as a solution in an organicsolvent (preferably EtOAc). Hydrogen gas is bubbled through the reactionmixture for about 5-20 min (preferably about 5 min) and the mixture isstirred under a hydrogen atmosphere for about 12-60 h (preferably about48 h). In cases where the reaction does not proceed to completion asmonitored by TLC, LC/MS, or HPLC, the hydrogen source is removed, thereaction mixture is bubbled with nitrogen for about 5-20 min (preferablyabout 5 min) and then filtered through a pad of Celite®, and thefiltrate is concentrated under reduced pressure. The crude material isre-subjected to the previously described reaction conditions for about2-20 h (preferably about 5 h). The hydrogen source is removed and themixture is bubbled with nitrogen for about 5-20 min (preferably about 5min) and then filtered through a pad of Celite®. The filter cake isrinsed with an organic solvent (preferably EtOAc) and the filtrate isconcentrated under reduced pressure to give the crude product. The crudematerial is optionally purified by precipitation, crystallization,and/or trituration from an appropriate solvent or solvents and/or bychromatography to give the target compound.

Illustration of General Procedure DD

Preparation #DD.1: Ethyl 2-ethyl-4-oxocyclopentanecarboxylate

A round-bottom flask was charged with 10% palladium on carbon (10 g, 9.4mmol). The flask was cooled to about 0° C. and EtOAc (400 mL) was addedunder a nitrogen atmosphere. The cooling bath was removed and ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate (47.8 g, 263 mmol, Preparation#CC.1) was added. Hydrogen gas was bubbled through the mixture for about5 min and the mixture was then stirred under a hydrogen atmosphere forabout 48 h. The hydrogen source was removed and the mixture was bubbledwith nitrogen for about 5 min and was filtered through a pad of Celite®.The filter cake was rinsed with EtOAc (400 mL). The filtrate wasconcentrated under reduced pressure to give ethyl2-ethyl-4-oxocyclopentanecarboxylate (about 9:1 mixture cis:trans) (48.0g, 99%) as a yellow liquid: ¹H NMR (CDCl₃) δ 4.23-4.10 (m, 2H), 3.22 (m,1H), 2.59-2.50 (m, 1H), 2.44-2.28 (m, 3H), 2.26-2.16 (m, 1H), 1.58-1.46(m, 1H), 1.41-1.30 (m, 1H), 1.30-1.23 (m, 3H), 1.02-0.91 (m, 3H).

General Procedure EE: Reductive Amination of a Ketone or an Aldehyde

A round-bottom flask is charged with a ketone or an aldehyde (1-40equiv; preferably 1 equiv) in an organic solvent (such as DCE, MeCN,MeOH, or MeCN/MeOH; preferably DCE). The mixture is optionally cooled toabout −10-10° C. (preferably about 0° C.) and AcOH (1-3 equiv;preferably 1.5 equiv) and an amine (1-3 equiv, preferably 1 equiv) areadded drop-wise, followed by the portion-wise addition of a suitablereducing agent such as sodium triacetoxyborohydride, sodiumcyanoborohydride, sodium borohydride, preferable sodium triacetoxyborohydride (1-6 equiv, preferably 1.5 equiv). Alternatively, to asolution of an amine (1-3 equiv, preferably 1 equiv) in an organicsolvent (such as DCE, MeCN, or MeOH; preferably DCE) is added a ketoneor an aldehyde (1-40 equiv; preferably 1 equiv) followed by subsequentportion-wise addition of an appropriate reducing agent such as sodiumtriacetoxyborohydride, sodium cyanoborohydride, sodium borohydride,preferable sodium triacetoxyborohydride (1-6 equiv, preferably 1.5equiv). The mixture is stirred for about 5-20 min (preferably about 15min) followed by the drop-wise addition of AcOH (1-3 equiv; preferably1.5 equiv). If the reaction mixture becomes too viscous to stir freely,additional organic solvent (such as DCE, MeCN, MeOH, or MeCN/MeOHmixture; preferably DCE) is optionally added to aid stirring. Thereaction mixture is stirred at room temperature for about 1-48 h(preferably about 20 h). The reaction mixture is slowly poured into asolution of aqueous base (such as saturated aqueous NaHCO₃) followed byoptional addition of solid NaHCO₃ and stirred for about 0.5-3 h(preferably about 2 h). The layers are separated and the organicsolution is dried over anhydrous Na₂SO₄ or MgSO₄, filtered, andconcentrated to dryness under reduced pressure. The crude material isoptionally purified by precipitation, crystallization, and/ortrituration from an appropriate solvent or solvents and/or bychromatography to give the target compound.

Illustration of General Procedure EE

Preparation #EE.1: Ethyl4-(dibenzylamino)-2-ethylcyclopentanecarboxylate

A round-bottom flask was charged with ethyl2-ethyl-4-oxocyclopentanecarboxylate (95.9 g, 521 mmol, Preparation#DD.1) and DCE (1.8 L). The solution was cooled to about 0° C. and AcOH(45 mL, 780 mmol) and dibenzylamine (120 mL, 625 mmol) were addeddrop-wise, resulting in formation of a thick suspension. The reactionmixture was warmed to about 10° C. and additional DCE (500 mL) wasadded. Sodium triacetoxyborohydride (166 g, 781 mmol) was addedportion-wise and the reaction mixture was stirred at room temperaturefor about 20 h. The reaction mixture was slowly poured into stirredsaturated aqueous NaHCO₃ (1.5 L), followed by the portion-wise additionof solid sodium bicarbonate (175 g,). The mixture was stirred for about2 h and the organic layer was separated, dried over anhydrous Na₂SO₄,and concentrated to dryness under reduced pressure. The crude yellow oilwas purified by silica gel chromatography using EtOAc/heptane as eluant(0-20% EtOAc in heptane). The solvent was removed under reduced pressureto yield ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (136.6g, 72%) as a white solid: LC/MS (Table 2, Method a) R_(t)=3.26 min; MSm/z: 366 (M+H)+

General Procedure FF: Debenzylation of an Amine

To a slurry of a palladium catalyst (for example Pd(OH)₂—C or Pd/C;preferably Pd(OH)₂—C) (0.01-0.1 equiv, preferably 0.02 equiv) in anorganic solvent (preferably EtOH) is added a dibenzylamine compound(preferably 1 equiv). The mixture is shaken or stirred at about 25-60°C. (preferably about 50° C.) for about 1-96 h (preferably about 1.5 h)at about 30-60 psi H₂ (preferably about 30 psi H₂). After removal of theH₂ source, the mixture is filtered through a pad of Celite® and thefiltrate is concentrated under reduced pressure to give the desiredproduct. The crude material is optionally purified by precipitation,crystallization, and/or trituration from an appropriate solvent orsolvents and/or by chromatography to give the target compound.

Illustration of General Procedure FF

Preparation #FF.1: Ethyl 4-amino-2-ethylcyclopentanecarboxylate

To a vessel containing a slurry of 20% Pd(OH)₂—C (12.9 g, 92.0 mmol) inEtOH (1.0 L) was added ethyl4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (129 g, 352 mmol,Preparation #EE.1). The reaction was shaken for about 90 min at about50° C. under about 30 psi of H₂. After removal of the H₂ source, theresulting mixture was filtered through a pad of Celite® and the filtratewas concentrated under reduced pressure to give ethyl4-amino-2-ethylcyclopentanecarboxylate (64.5 g, 99%) as a yellow syrup:¹H NMR (CDCl₃) δ 4.03-3.88 (m, 2H), 3.17 (m, 1H), 2.68 (m, 1H),2.09-2.02 (m, 2H), 2.02-1.94 (m, 2H), 1.84 (m, 1H), 1.58-1.48 (m, 1H),1.32-1.18 (m, 1H), 1.09 (m, 3H), 1.03 (m, 2H), 0.78-0.69 (m, 3H).

General Procedure GG: Hydrolysis of an Ester to a Carboxylic Acid

To a flask containing an ester (preferably 1 equiv) either neat or in anorganic solvent (such as 1,4-dioxane, MeOH, or THF/MeOH, preferably1,4-dioxane) is added an aqueous base (such as aqueous NaOH or LiOH,1-10 equiv, preferably 2-6 equiv). The mixture is stirred at about0-100° C. (preferably ambient temperature) for about 1-12 h (preferablyabout 4-8 h). The reaction mixture is then acidified with the additionof a suitable aqueous acid (such as aqueous HCl). The layers areseparated and the aqueous layer is optionally extracted with additionalorganic solvent (such as EtOAc or DCM, preferably DCM). The organiclayer or layers are optionally dried over anhydrous Na₂SO₄ or MgSO₄,filtered, and concentrated to dryness under reduced pressure to givecrude target compound. Alternatively, the reaction mixture isconcentrated under reduced pressure to give crude target compound as acarboxylate salt. The crude material is optionally purified byprecipitation, crystallization, and/or trituration from an appropriatesolvent or solvents and/or by chromatography to give the targetcompound.

Illustration of General Procedure GG

Preparation #GG.1:(1S,2R,4S)-4-(Cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylicacid

To a flask containing (1S,2R,4S)-ethyl4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylate (11.1 g, 38.4mmol, Example #15, Step F) was added aqueous NaOH (1 N, 210 mL, 210mmol). After stirring at ambient temperature for about 8 h, the reactionwas acidified to about pH 1 using 6 N aqueous HCl and extracted with DCM(3×150 mL). The combined organic layers were washed with brine, driedover anhydrous MgSO₄, filtered, and concentrated under reduced pressureto give(1S,2R,4S)-4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylicacid with 25 mol % DCM as an excipient (10.7 g, 99%): LC/MS (Table 2,Method a) R_(t)=1.71 min; MS m/z: 260 (M−H)⁻.

General Procedure HH: Dehydration of an Amide to a Nitrile

A mixture of a benzamide (preferably 1 equiv) and a dehydrating agent(preferably POCl₃) (10-30 equiv; preferably 20 equiv) is heated at about30-80° C. (preferably about 60° C.) with stirring for about 1-3 h(preferably about 1 h). The reaction mixture is then concentrated todryness under reduced pressure. The resulting crude product ispartitioned between an organic solvent (such as EtOAc) and saturatedaqueous NaHCO₃ solution. The layers are separated, and the organicsolution is washed with brine and dried over anhydrous Na₂SO₄ or MgSO₄,filtered, and concentrated to dryness under reduced pressure. The crudematerial is optionally purified by precipitation, crystallization,and/or trituration from an appropriate solvent or solvents and/or bychromatography to give the target compound.

Illustration of General Procedure HH

Preparation #HH.1: 6-Chloro-4-(trifluoromethyl)nicotinonitrile

A mixture of 6-chloro-4-(trifluoromethyl)nicotinamide (0.847 g, 3.77mmol, Preparation #27) and POCl₃ (7.03 mL, 75.0 mmol) was heated atabout 60° C. with stirring for about 1 h. The reaction mixture wascooled to ambient temperature and concentrated to dryness under reducedpressure and the resulting material was partitioned between chilledsaturated aqueous NaHCO₃ (30 mL) and EtOAc (30 mL). The layers wereseparated and the organic solution was washed with saturated aqueousNaHCO₃ solution (30 mL) and brine (30 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated to dryness under reduced pressure to give6-chloro-4-(trifluoromethyl)nicotinonitrile (0.67 g, 86%) as a brownliquid: LC/MS (Table 2, Method a) R_(t)=2.31 min: ¹H NMR (CDCl₃) δ 8.87(s, 1H), 7.75 (s, 1H).

General Procedure II: Chiral Preparative HPLC Purification

Chiral purification is performed using Varian 218 LC pumps, a Varian CVM500 with switching valves and heaters for automatic solvent, column andtemperature control and a Varian 701 Fraction collector. Detectionmethods include a Varian 210 variable wavelength detector, an in-linepolarimeter (PDR-chiral advanced laser polarimeter, model ALP2002) usedto measure qualitative optical rotation (+/−) and an evaporative lightscattering detector (ELSD) (a PS-ELS 2100 (Polymer Laboratories)) usinga 100:1 split flow. ELSD settings are as follows: evaporator: 46° C.,nebulizer: 24° C. and gas flow: 1.1 SLM.

TABLE II.1 Examples prepared using General Procedure II from racematesR_(t) min (Table 2, m/z ESI+ Racemate Product Ex. # Method) (M + H)⁺ Ex.N-((1R,3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3- II.1.1 1.77 (a) 375 #H.1.55e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide [Table 3, Method 4, R_(t) 22 min,or = positive] Ex. N-((1S,3S,4R)-3-(6H-Imidazo[1,5- II.1.2 1.81 (a) 360#H.1.56 a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyclopentyl)cyclopropanesulfonamide [Table 3, Method 4, R_(t) 31min, or = negative] Ex. N-((1R,3R,4S)-3-(6H-Imidazo[1,5- II.1.3 1.82 (a)360 #H.1.56 a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyclopentyl)cyclopropanesulfonamide [Table 3, Method 4, R_(t) 34min, or = positive] Ex. N-((1R,4S)-3,3-Dimethyl-4-(6H-pyrrolo[2,3-II.1.4 1.77 (a) 375 #H.1.53 e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide [Table 3, Method 7, R_(t) 13.5min, or = negative] Ex. N-((1S,4R)-3,3-Dimethyl-4-(6H-pyrrolo[2,3-II.1.5 1.77 (a) 375 #H.1.53 e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide [Table 3, Method 7, R_(t) 15.5min, or = negative] Ex. N-((1S,3R,4S)-3-Ethyl-4-(6H-imidazo[1,5- II.1.61.94 (a) 374 #H.1.57 a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide [Table 3, Method 8, R_(t) 16.5min, or = negative] Ex. N-((1R,3S,4R)-3-Ethyl-4-(6H-imidazo[1,5- II.1.71.95 (a) 374 #H.1.57 a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide [Table 3, Method 8, R_(t) 23.5min, or = positive] Ex. N-((1R,3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3- II.1.81.75 (a) 389 #H.1.19 e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclobutanesulfonamide [Table 3, Method 6, R_(t) 14.0min, or = positive] Ex. N-((1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3- II.1.91.75 (a) 389 #H.1.19 e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclobutanesulfonamide [Table 3, Method 6, R_(t) 17.0min, or = negative] Ex. N-((1R,3S,4R)-3-Ethyl-4-(6H-pyrrolo[2,3- II.1.101.83 (a) 403 #H.1.20 e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopentanesulfonamide [Table 3, Method 6, R_(t) 14.0min, or = positive] Ex. N-((1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3- II.1.111.83 (a) 403 #H.1.20 e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopentanesulfonamide [Table 3, Method 6, R_(t) 17.0min, or = negative] Ex. N-((1S,3R,4S)-3-Ethyl-4-(3-methyl-6H- II.1.121.93 (a) 388 #H.1.61 imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide [Table 3, Method 1, R_(t) 20.0min, or = negative] Ex. N-((1R,3S,4R)-3-Ethyl-4-(3-methyl-6H- II.1.131.93 (a) 388 #H.1.61 imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide [Table 3, Method 1, R_(t) 19.0min, or = positive] Ex. N-((1R,3S,4R)-3-Methyl-4-(6H-pyrrolo[2,3-II.1.14 1.62 (a) 361 #H.1.52 e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide [Table 3, Method 3, R_(t) = 12.0min, or = positive] Ex. 3-((3S,4S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-II.1.15 1.05 (a) 256 #L.3.10 e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-3-oxopropanenitrile [Table 3, Method 9, R_(t) = 7.8 min, or = negative]

TABLE II.2 Examples prepared using General Procedure II to separatescalemic mixtures R_(t) min m/z ESI+ Scalemic Mixture Product Ex. #(method) (M + H)⁺ 4-Cyano-N-((1R,3S)-2,2-dimethyl-3- 4-Cyano-N-((1R,3S)-II.2.1 1.88 (a) 422 (6-tosyl-6H-pyrrolo[2,3- 2,2-dimethyl-3-(6H-e][1,2,4]triazolo[4,3-a]pyrazin-1- pyrrolo[2,3-yl)cyclobutyl)benzenesulfonamide e][1,2,4]triazolo[4,3- (prepared usingA from (1S,3R)-3- a]pyrazin-1- acetamido-2,2-yl)cyclobutyl)benzenesulfonamide dimethylcyclobutanecarboxylic acid(Table 3, [prepared as described in Tetrahedron: Method 5, R_(t) = 16.0min, Asymmetry 2008, 19, 302-308] and or = negative) Preparation #9,EDC, C with DIEA, JJ, N with 4-cyanobenzene-1-sulfonyl chloride[Maybridge], DIEA, H) 4-Cyano-N-((1R,3S)-2,2-dimethyl-3-4-Cyano-N-((1S,3R)- II.2.2 1.88 (a) 422 (6-tosyl-6H-pyrrolo[2,3-2,2-dimethyl-3-(6H- e][1,2,4]triazolo[4,3-a]pyrazin-1- pyrrolo[2,3-yl)cyclobutyl)benzenesulfonamide e][1,2,4]triazolo[4,3- (prepared usingA from (1S,3R)-3- a]pyrazin-1- acetamido-2,2-yl)cyclobutyl)benzenesulfonamide dimethylcyclobutanecarboxylic acid(Table 3, [prepared as described in Tetrahedron: Method 5, R_(t) = 11.0min, Asymmetry 2008, 19, 302-308] and or = positive) Preparation #9,EDC, C with DIEA, JJ, N with 4-cyanobenzene-1-sulfonyl chloride[Maybridge], DIEA, H) 6-((1R,3S)-2,2-Dimethyl-3-(6-tosyl-6-((1S,3R)-2,2- II.2.3 1.87 (a) 3596H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- Dimethyl-3-(6H- a]pyrazin-1-pyrrolo[2,3- yl)cyclobutylamino)nicotinonitrile e][1,2,4]triazolo[4,3-(prepared using A from (1S,3R)-3- a]pyrazin-1- acetamido-2,2-yl)cyclobutylamino)nicotinonitrile dimethylcyclobutanecarboxylic acid(Table 3, [prepared as described in Tetrahedron: Method 2, R_(t) = 6.4min, Asymmetry 2008, 19, 302-308] and or = positive) Preparation #9,EDC, C with DIEA, JJ, O with 6-fluoronicotinonitrile [Matrix], H)6-((1R,3S)-2,2-Dimethyl-3-(6-tosyl- 6-((1R,3S)-2,2- II.2.4 1.87 (a) 3596H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- Dimethyl-3-(6H- a]pyrazin-1-pyrrolo[2,3- yl)cyclobutylamino)nicotinonitrile e][1,2,4]triazolo[4,3-(prepared using A from (1R,3S)-3- a]pyrazin-1- acetamido-2,2-yl)cyclobutylamino)nicotinonitrile dimethylcyclobutanecarboxylic acid(Table 3, [prepared as described in Tetrahedron: Method 2, R_(t) = 8.8min, Asymmetry 2008, 19, 302-308] and or = negative) Preparation #9,EDC, C with DIEA, JJ, O with 6-fluoronicotinonitrile [Matrix], H)General Procedure JJ: Acidic Hydrolysis of an Acetyl Protected Amine

To a solution of an N-acetamide (preferably 1 equiv) in an organicsolvent (such as 1,4-dioxane) is added an acid, such as 6 N aqueous HCl(3-100 equiv, preferably 40 equiv). The reaction mixture is heated atabout 60-100° C. (preferably about 100° C.) for about 1-24 h (preferablyabout 16 h). The reaction mixture is allowed to cool to ambienttemperature before it is partitioned between an organic solvent (such asEtOAc or DCM) and aqueous base (such as NaHCO₃, Na₂CO₃ or NaOH,preferably NaHCO₃) and the aqueous layer is optionally extracted withadditional organic solvent (such as EtOAc or DCM). The organic layer isdried over anhydrous MgSO₄ or Na₂SO₄, filtered, and concentrated underreduced pressure. The crude material is optionally purified byprecipitation, crystallization, and/or trituration from an appropriatesolvent or solvents and/or by chromatography to give the targetcompound.

Illustration of General Procedure JJ

Preparation #JJ.1:(1R,3S)-2,2-Dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutanamine

To a solution ofN-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)acetamide(2.20 g, 4.86 mmol, prepared using A from Preparation #9 and(1S,3R)-3-acetamido-2,2-dimethylcyclobutanecarboxylic acid [prepared asdescribed in Tetrahedron: Asymmetry 2008, 19, 302-308] with EDC, C withDIEA) in 1,4-dioxane (30 mL) was added 6 N aqueous HCl (32.4 mL, 194mmol). The reaction was heated at about 100° C. for about 16 h. Thereaction was allowed to cool to ambient temperature and was partitionedbetween EtOAc (500 mL) and aqueous NaHCO₃ (500 mL). The organic layerwas dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure to give(1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutanamine(1.56 g, 78%) as a tan solid: LC/MS (Table 2, Method a) R_(t)=1.60 min;MS m/z: 411 (M+H)⁺.

General Procedure KK: Cyclopropanation Using Chloroiodomethane

To an alkene, cycloalkene, or α,β-unsaturated ketone (preferably 1equiv) in an organic solvent (for example, Et₂O, toluene, or DCM,preferably DCM) is added diethylzinc (preferably 1.1 M in toluene, 1-10equiv, preferably 5 equiv) drop-wise. The reaction mixture is stirred atambient temperature for about 10-40 min (preferably about 10 min). Thereaction mixture is cooled to about 0° C., followed by the drop-wiseaddition of a solution of chloroiodomethane (1-10 equiv, preferably 5equiv) in an organic solvent (for example, Et₂O, toluene, or DCM,preferably DCM). The reaction mixture is warmed to ambient temperatureand stirred for about 1-20 h (preferably about 18 h). To the reactionmixture is then added saturated aqueous NH₄Cl and stirred for about10-60 minutes (preferably about 20 min). The resulting mixture isextracted with an organic solvent (preferably DCM). The organic layer isoptionally washed with saturated aqueous NaHCO₃ and/or brine. In allcases, the solution is dried over anhydrous Na₂SO₄ or MgSO₄, thendecanted or filtered prior to concentrating under reduced pressure. Thecrude material is optionally purified by precipitation, crystallization,and/or trituration from an appropriate solvent or solvents and/or bychromatography to give the target compound.

Illustration of General Procedure KK

Preparation #KK.1: (1R,2S,4R,5S)-Methyl4-(ethoxycarbonylamino)bicyclo[3.1.0]hexane-2-carboxylate

To (1S,4R)-4-(tert-butoxycarbonylamino)cyclopent-2-enecarboxylic acid(2.70 g, 11.8 mmol, Preparation #17) in DCM (170 mL) was slowly addeddiethylzinc (1.1 M in toluene, 54.0 mL, 59.4 mmol). The mixture wasstirred for about 10 min at ambient temperature, cooled to about 0° C.,and treated drop-wise with a solution of chloroiodomethane (4.30 mL,59.4 mmol) in DCM (24 mL). The reaction mixture was allowed to warm toroom temperature and was stirred for about 18 h. Saturated aqueous NH₄Cl(10 mL) was added and the mixture was stirred for about 20 min. Thelayers were separated and the aqueous layer was further extracted withDCM (20 mL). The combined organic layers were washed with brine (20 mL),dried over anhydrous MgSO₄, filtered, and concentrated under reducedpressure. The crude material was purified by silica gel chromatographyeluting with a gradient of 0-100% EtOAc/heptane to afford(1R,2S,4R,5S)-methyl4-(ethoxycarbonylamino)bicyclo[3.1.0]hexane-2-carboxylate (0.95 g, 35%):LC/MS (Table 2, Method a) R_(t)=1.88 min; MS m/z: 228 (M+H)⁺.

General Procedure LL.1: Formation of a Bromomethyl Ketone from an AcidChloride Using 1-methyl-3-nitro-1-nitrosoguanidine

To a mixture of an aqueous base (such as 45% KOH) (100-200 equiv,preferably 125 equiv) and an organic solvent (such as Et₂O) at about−20-20° C. (preferably about 0° C.) is added1-methyl-3-nitro-1-nitrosoguanidine [TCI] (5-20 equiv, preferably 12equiv) portion-wise to generate CH₂N₂ in situ. After about 0.5-2.0 h(preferably about 0.5 h) the layers are separated and the organic layeris added slowly to a solution of an appropriately substituted acidchloride (preferably 1 equiv) in an organic solvent (such as THF,1,4-dioxane or Et₂O, preferably THF) at about −20-20° C. (preferablyabout 0° C.). The reaction mixture is stirred for about 0.5-2.0 h(preferably about 0.5 h) at about −20-20° C. (preferably about 0° C.)before the drop-wise addition of 48% aqueous HBr (10-40 equiv,preferably 14 equiv). After about 15-30 min, (preferably about 15 min)the reaction mixture is washed with brine after optional addition of anorganic solvent (such as EtOAc). The organic layer is dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Thecrude material is optionally purified by precipitation, crystallization,and/or trituration from an appropriate solvent or solvents and/or bychromatography to give the target compound.

Illustration of General Procedure LL.1

Preparation #LL.1.1(R)-(9H-Fluoren-9-yl)methyl3-(2-bromoacetyl)piperidine-1-carboxylate

To a mixture of 45% aqueous KOH (30 mL, 2.70 mmol) and Et₂O (100 mL) atabout 0° C. 1-methyl-3-nitro-1-nitrosoguanidine (5.0 g, 34 mmol, TCI)was added portion-wise. After about 30 min the layers were separated andthe organic layer was added slowly to a solution of(R)-(9H-fluoren-9-yl)methyl 3-(chlorocarbonyl)piperidine-1-carboxylate(1.0 g, 2.7 mmol) prepared using W from(R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-3-carboxylic acid(Fluka) in THF (10 mL). The reaction mixture was slowly stirred forabout 30 min at about 0° C. before the drop-wise addition of 48% aqueousHBr (2.0 mL, 37 mmol). After about 15 min, the reaction mixture waswashed with brine (2×100 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure to give(R)-(9H-fluoren-9-yl)methyl 3-(2-bromoacetyl)piperidine-1-carboxylate(1.10 g, 95%) as a clear oil: LC/MS (Table 2, Method a) R_(t)=2.59 min;MS m/z: 428/430 (M+H)⁺.

General Procedure LL.2: Formation of a Bromomethyl Ketone from an AcidChloride Using Trimethylsilyldiazomethane

A solution of an appropriately substituted acid chloride (preferably 1equiv) in an organic solvent (such as THF, MeCN, Et₂O, or THF/MeCN,preferably THF/MeCN) is added to a solution of 2.0 Mtrimethylsilyldiazomethane (2 M in Et₂O) (2-10 equiv, preferably 4equiv) at about −20-20° C. (preferably about 0° C.) in a suitableorganic solvent such as THF, MeCN, Et₂O, or THF/MeCN, preferablyTHF/MeCN). The reaction mixture is stirred for about 0.5-5 h (preferablyabout 4 h) at about −20-20° C. (preferably about 0° C.) before thedrop-wise addition of 48% aqueous HBr (5-40 equiv, preferably 10 equiv).After about 0-30 min, (preferably about 0 min) the reaction mixture canbe concentrated to dryness to give the desired product or is optionallywashed with brine after optional addition of an organic solvent (such asEtOAc). In cases where the reaction mixture is subjected to an aqueouswork-up, the organic layer is dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude material is optionallypurified by precipitation, crystallization, and/or trituration from anappropriate solvent or solvents and/or by chromatography to give thetarget compound.

Illustration of General Procedure LL.2

Preparation #LL.2.1(R)-(9H-Fluoren-9-yl)methyl3-(2-bromoacetyl)piperidine-1-carboxylate

(R)-(9H-fluoren-9-yl)methyl 3-(chlorocarbonyl)piperidine-1-carboxylate(4.21 g, 11.4 mmol, prepared using W from(R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-3-carboxylic acid[Fluka]) was dissolved in a mixture of THF and MeCN (1:1, 16 mL) andadded to a solution of trimethylsilyldiazomethane (2 M in Et₂O, 22.8 mL,45.5 mmol) and THF/MeCN (1:1, 16 mL) at about 0° C. The resultingmixture was stirred at about 0° C. for about 4 h followed by thedrop-wise addition of HBr (48% aqueous solution, 6.2 mL, 114 mmol). Theorganic solvents were removed and the precipitate was collected byfiltration and dried in air to give (R)-(9H-fluoren-9-yl)methyl3-(2-bromoacetyl)piperidine-1-carboxylate (4.46 g, 92%): LC/MS (Table 2,Method a) R_(t)=2.59 min; MS m/z: 428/430 (M+H)⁺.

General Procedure MM: Reduction of α,β-Unsaturated Ketone to an AllylicAlcohol

A round-bottomed flask is charged with an α,β-unsaturated ketone(preferably 1 equiv), an organic solvent (such as MeOH or EtOH,preferably MeOH) and cerium(III) chloride heptahydrate (1-2 equiv,preferably 1.25 equiv) followed by portion-wise addition of a reducingagent such as sodium borohydride (1-2 equiv, preferably 1.25 equiv). Theresulting mixture is stirred at room temperature for about 5-24 h(preferably about 16 h). The reaction mixture is quenched with anaqueous acid (such as saturated aqueous NH₄Cl). The mixture is stirredfor about 5-30 min (preferably about 10 min), followed by the additionof an organic solvent (such as Et₂O). The layers are separated and theaqueous layer is extracted with an organic solvent (such as Et₂O). Thecombined organic layers are washed with saturated aqueous NaHCO₃, driedover anhydrous Na₂SO₄ or MgSO₄, filtered, and concentrated to drynessunder reduced pressure. The crude material is optionally furtherpurified by precipitation, crystallization, or trituration from anappropriate solvent or solvents or by chromatography to give the targetcompound.

Illustration of General Procedure MM

Preparation #MM.1: cis andtrans-Ethyl-4-hydroxy-2-methylcyclopent-2-enecarboxylate

A round-bottom flask was charged with ethyl2-methyl-4-oxocyclopent-2-enecarboxylate (2.04 g, 12.1 mmol, Preparation#CC.1), MeOH (30 mL), and cerium(III) chloride heptahydrate (5.65 g,15.2 mmol) followed by portion-wise addition of sodium borohydride(0.574 g, 15.2 mmol). The suspension was stirred at room temperatureover about 16 h. Saturated aqueous NH₄Cl solution (50 mL) was added. Themixture was stirred for about 10 min and Et₂O (60 mL) was added. Thelayers were separated and the aqueous layer was extracted with Et₂O(3×30 mL). The combined organic layers were washed with saturatedaqueous NaHCO₃, dried over anhydrous MgSO₄, filtered, and concentratedto dryness under reduced pressure. The residue was purified via silicagel chromatography eluting with 20-60% EtOAc/pentane to yield cis-ethyl4-hydroxy-2-methylcyclopent-2-enecarboxylate (0.96 g, 46%): ¹H NMR (400MHz, CDCl₃) δ 5.77-5.71 (m, 1H), 4.63 (m, 1H), 4.28-4.11 (m, 2H),3.27-3.20 (m, 1H), 2.59 (bs, 1H), 2.41-2.30 (m, 1H), 2.00 (d, J=14.2 Hz,1H), 1.79 (d,=1.2 Hz, 3H), 1.30 (t, J=7.1 Hz, 3H) and trans-ethyl4-hydroxy-2-methylcyclopent-2-enecarboxylate (0.69 g, 33%): ¹H NMR (400MHz, CDCl₃) δ 5.63 (dd, J=1.8, 3.4 Hz, 1H), 4.98 (m, 1H), 4.20-4.11 (m,2H), 3.60-3.53 (m, 1H), 2.57 (ddd, J=4.4, 7.1, 13.9 Hz, 1H), 1.98 (ddd,J=3.5, 8.4, 13.9 Hz, 1H), 1.80 (d, J=1.4, 3H), 1.46 (bs, 1H), 1.27 (t,J=7.1 Hz, 3H).

Example #11-(2-Methylcyclohexyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a solution of5-(4-tert-butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine(0.40 g, 1.2 mmol, Preparation #3) and DIEA (0.20 mL, 1.2 mmol) in1,4-dioxane (12 mL) at about 0° C. was added 2-methylcyclohexanecarbonylchloride (0.19 g, 1.2 mmol, Preparation #4). After the completeaddition, the ice bath was removed and the reaction was allowed to warmto ambient temperature. After about 1 h, SOCl₂ (0.42 mL, 5.8 mmol) wasadded and the reaction was heated at about 90° C. for about 1 h. Thereaction was allowed to cool to ambient temperature and then aqueousNa₂CO₃ (2 M, 11.6 mL, 23.2 mmol) and MeOH (12 mL) were added. Thereaction was heated at about 90° C. for about 3 days. The reaction wasconcentrated under reduced pressure to remove MeOH and then partitionedbetween EtOAc (50 mL) and saturated aqueous NaHCO₃ (40 mL). The organiclayer was separated and dried over anhydrous Na₂SO₄ and the solvent wasconcentrated under reduced pressure. The residue was purified oversilica gel (12 g) using EtOAc as the eluent and then further purified byRP-HPLC (Table 2, Method b). The combined product-containing fractionswere concentrated under reduced pressure to remove the MeCN and theresulting precipitate was collected by vacuum filtration to afford1-(2-methylcyclohexyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineas a white solid (0.10 g, 35%): LC/MS (Table 2, Method a) R_(t)=1.84min; MS m/z: 256 (M+H)⁺.

Example #21-(Piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

Step A: Benzyl4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidine-1-carboxylate

Benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate (0.41 g, 1.4 mmol,Preparation #5) was added to a solution of5-(4-tert-butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine(0.50 g, 1.4 mmol, Preparation #3) and DIEA (0.25 mL, 1.4 mmol) in1,4-dioxane (15 mL) at about 0° C. After the complete addition, the icebath was removed and the reaction was allowed to warm to ambienttemperature. After about 1 h, SOCl₂ (0.53 mL, 7.2 mmol) was added andthe reaction was heated at about 90° C. for about 1 h. The reaction wasallowed to cool to ambient temperature then aqueous Na₂CO₃ (2 M, 14.5mL, 29.0 mmol) was added and the reaction was heated at about 90° C. forabout 3 days. The reaction was partitioned with EtOAc (50 mL) andsaturated aqueous NaHCO₃ (40 mL). The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified over silica gel (12 g) eluting with 50-100% EtOAc inheptane to afford benzyl4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidine-1-carboxylateas a yellow solid (0.34 g, 61%): LC/MS (Table 2, Method a) R_(t)=1.89min; MS m/z: 377 (M+H)⁺.

Step B:1-(Piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

Benzyl4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidine-1-carboxylate(0.34 g, 0.90 mmol) and 10% Pd on carbon (0.10 g, 0.09 mmol) in MeOH (30mL) were shaken under hydrogen at about 60 psi for about 5 h. The H₂source was removed, and the reaction was filtered through Celite® andconcentrated under reduced pressure to give1-(piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine as ayellow solid (0.18 g, 77%): LC/MS (Table 2, Method a) R_(t)=0.70 min; MSm/z: 243 (M+H)⁺.

Example #33-(4-(6H-Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidin-1-yl)-3-oxopropanenitrile

To a suspension of1-(piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.090 g, 0.37 mmol, Example #2) and pyridine (0.12 mL, 1.5 mmol) in DMF(5 mL) was added perfluorophenyl 2-cyanoacetate (0.14 g, 0.56 mmol,Preparation #6). After about 3 h at ambient temperature, the reactionmixture was quenched with MeOH (0.5 mL) and then purified by RP-HPLC(Table 2, Method b). The appropriate fractions were concentrated andlyophilized to afford3-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidin-1-yl)-3-oxopropanenitrileas a white solid (0.005 g, 4%): LC/MS (Table 2, Method a) R_(t)=1.24min; MS m/z: 310 (M+H)⁺.

Example #41-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a suspension of1-(piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.090 g, 0.37 mmol, Example #2) and pyridine (0.12 mL, 1.5 mmol) in DMF(5 mL) was added cyclopropanesulfonyl chloride (0.060 g, 0.41 mmol).After about 3 h at ambient temperature, the reaction mixture wasquenched with MeOH (0.5 mL) and then purified by RP-HPLC (Table 2,Method b). The appropriate fractions were concentrated and lyophilizedto afford 1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2, 4]triazolo[4,3-a]pyrazine as a white solid (0.008 g, 6%): LC/MS(Table 2, Method a) R_(t)=1.52 min; MS m/z: 347 (M+H)⁺.

Example #5 1-Cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a solution of5-(4-tert-butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine(0.39 g, 1.1 mmol; Preparation #3) and DIEA (0.20 mL, 1.1 mmol) in1,4-dioxane (12 mL) at about 0° C. was added cyclohexanecarbonylchloride (0.17 g, 1.1 mmol). The reaction was then warmed to ambienttemperature for about 1 h. SOCl₂ (0.41 mL, 5.6 mmol) was added and thereaction was heated to about 90° C. for about 1 h. The reaction wascooled to ambient temperature and aqueous Na₂CO₃ (2 M, 12 mL, 24 mmol)was added slowly followed by 1,4-dioxane (5 mL). The reaction was heatedat about 60° C. for about 72 h. The reaction was cooled to ambienttemperature and concentrated under reduced pressure. The crude productwas diluted with EtOAc (40 mL) and washed with saturated aqueous NaHCO₃(40 mL) and brine (40 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography eluting with a gradient of 0-100%heptane/EtOAc (12 g column) and dried in a vacuum oven at about 55° C.for about 18 h to give1-cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.109 g,40%): LC/MS (Table 2, Method a) R_(t)=1.66 min; MS m/z: 242 (M+H)⁺.

Example #6N-((1S,3R)-3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide

Step A: tert-Butyl(1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate

To mixture of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.50 g,8.24 mmol, Preparation #9) and(1R,3S)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (2.08 g,9.07 mmol, Peptech) in DCM (30 mL) was added EDC.HCl (1.90 g, 9.89mmol). After about 4.5 h, water (30 mL) was added and the layers wereseparated. The aqueous layer was then extracted with EtOAc (15 mL). Thecombined organic layers were washed with brine, dried over anhydrousMgSO₄, filtered, and concentrated under reduced pressure. The crudematerial was dissolved in DCM (15 mL) and purified by silica gelchromatography eluting with a gradient of 40-100% EtOAc in heptane togive tert-butyl(1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate(4.20 g, 97%): LC/MS (Table 2, Method a) R_(t)=2.27 min; MS m/z: 515(M+H)⁺.

Step B: tert-Butyl(1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate

To a solution of tert-butyl(1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate(4.73 g, 9.19 mmol) in 1,4-dioxane (50 mL) was added TEA (5.10 mL, 36.8mmol) and SOCl₂ (1.34 mL, 18.4 mmol). The reaction mixture was heated atabout 80° C. After about 1.5 h, saturated aqueous Na₂CO₃ (100 mL) wasadded and heating was resumed at about 80° C. for about 6 h. Thereaction mixture was cooled to ambient temperature for about 3 days andthen heated at about 80° C. for about 16 h. Water and EtOAc (100 mLeach) were added and the layers were separated. The aqueous layer wasthen extracted with additional EtOAc (2×100 mL). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure. The crude solid was trituratedwith petroleum ether (b.p. 30-60° C.; 30 mL) and collected by vacuumfiltration, while washing with additional petroleum ether (b.p. 30-60°C.; 20 mL), to give tert-butyl(1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamateas a light brown solid (2.86 g, 86%): LC/MS (Table 2, Method a)R_(t)=1.75 min; MS m/z: 343 (M+H)⁺.

Step C:(1S,3R)-3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanaminehydrochloride

To a mixture of tert-butyl(1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate(1.57 g, 4.59 mmol) in 1,4-dioxane (45 mL) was added HCl (4 M in1,4-dioxane, 8.0 mL, 32.0 mmol). The reaction mixture was then heated atabout 60° C. After about 2 h, the reaction mixture was cooled to ambienttemperature, filtered, while washing with Et₂O (50 mL) and the solid wasdried in a vacuum oven overnight at about 60° C. to give(1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanaminehydrochloride (1.38 g, 95%): LC/MS (Table 2, Method a) R_(t)=0.74 min;MS m/z: 243 (M+H)⁺.

Step D:N-((1S,3R)-3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide

To a mixture of(1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanaminehydrochloride (0.300 g, 0.952 mmol) in DMF (9 mL) was added TEA (0.462mL, 3.33 mmol) and cyclopropanesulfonyl chloride (0.097 mL, 0.95 mmol).After about 1.5 h at ambient temperature, the reaction was diluted withwater (10 mL) and extracted with DCM (3×15 mL). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure. To the crude material was addedMeOH (˜50 mL) and a small amount of insoluble material (<0.01 g) wasfiltered. Silica gel (2 g) was added to the filtrate and the mixture wasconcentrated under reduced pressure. The silica mixture was purified bysilica gel chromatography eluting with a step-wise gradient ofDCM/MeOH/NH₄OH 990:9:1 to 980:18:2 to give an off-white solid that wasdried in a vacuum oven at about 70° C. The solid was dissolved in hotMeOH. The resulting material was filtered while hot to removeparticulates. The filtrate was sonicated while cooling to get a finesuspension which was then concentrated under reduced pressure and driedin a vacuum oven at about 100° C. to giveN-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide(0.21 g, 64%): LC/MS (Table 2, Method a) R_(t)=1.51 min; MS m/z: 347(M+H)⁺.

Example #7N-(4-(6H-Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamideStep A: tert-Butyl4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)bicyclo[2.2.2]octan-1-ylcarbamate

A round bottom flask was charged with2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (3.75 g, 11.1 mmol,Preparation #9),4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (3.0g, 11 mmol, Prime Organics), HATU (4.23 g, 11.1 mmol), TEA (6.2 mL, 44mmol), and DCM (65 mL). The reaction mixture was stirred at ambienttemperature for about 16 h. The reaction mixture was diluted with water(30 mL) and the layers were separated. The reaction mixture was filteredthrough Celite® and washed with DCM (60 mL). The organic layer waswashed with water (3×50 mL), dried over anhydrous MgSO₄, filtered, andconcentrated under reduced pressure. The crude material was purified bysilica gel chromatography eluting with a gradient of 0-100% EtOAc in DCMto afford tert-butyl4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)bicyclo[2.2.2]octan-1-ylcarbamateas a brown amorphous solid (5.38 g, 87%): LC/MS (Table 2, Method a)R_(t)=2.40 min; MS m/z 555 (M+H)⁺.

Step B:4-(6-Tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine

A round bottom flask was charged with tert-butyl4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)bicyclo[2.2.2]octan-1-ylcarbamate(5.38 g, 9.40 mmol), SOCl₂ (0.69 mL, 9.40 mmol), TEA (1.57 mL, 11.3mmol), and 1,4-dioxane (72 mL). The reaction mixture was heated at about80° C. for about 2 h. The reaction mixture was cooled to ambienttemperature and EtOAc (100 mL) was added and the layers were separated.The organic layer was washed with water (3×30 mL), dried over anhydrousMgSO₄, filtered, and concentrated under reduced pressure to give a crudemixture of tert-butyl4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamateand4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amineas a brown solid (8.5 g). To this crude mixture was added HCl (4 N in1,4-dioxane, 12 mL, 48.0 mmol), and 1,4-dioxane (56 mL). The reactionmixture was stirred at about 60° C. for about 4 h. Additional HCl (4 Min 1,4-dioxane, 12 mL, 48.0 mmol) was added and stirring was continuedat about 60° C. for about 3 h. The reaction mixture was cooled toambient temperature. The precipitate was filtered and washed with Et₂O(about 50 mL). The solid was stirred with NaHCO₃ (5% in water, 15 mL)for about 2 h. The solid was filtered, washed with water, and dried in avacuum oven at about 60° C. for about 15 h to give4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amineas a tan solid (2.95 g, 72% over 2 steps): LC/MS (Table 2, Method a)R_(t)=1.57 min; MS m/z 437 (M+H)⁺.

Step C:N-(4-(6-Tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide

A round bottom flask was charged with4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine(0.40 g, 0.92 mmol), TEA (0.51 mL, 3.7 mmol) in DCM (3 mL) and DMF (6mL). Cyclopropanesulfonyl chloride (0.16 g, 1.1 mmol) was addeddrop-wise and the resulting suspension was stirred at ambienttemperature for about 18 h. The solvent was removed under reducedpressure and DCM (10 mL) was added. The crude material was purified bysilica gel chromatography eluting with a gradient of 0-10% MeOH/DCM togiveN-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide(0.27 g, 55%): LC/MS (Table 2, Method a) R_(t)=2.14 min; MS m/z 541(M+H)⁺.

Step D:N-(4-(6H-Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide

A round bottom flask was charged withN-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide(0.27 g, 0.50 mmol), aqueous NaOH (1N, 1.0 mL, 1.0 mmol), and1,4-dioxane (8 mL). The reaction mixture was stirred at about 60° C. forabout 2 h. NH₄OAc (50 mM aqueous buffer, 2 mL) and DMF (7 mL) were addedand insoluble material was removed via filtration. The filtrate waspurified by RP-HPLC (Table 2, Method c). The appropriate fractions werecombined, the organic solvent was concentrated under reduced pressure,the resulting solid was collected by filtration, washed with water (20mL), and lyophilized to giveN-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamideas a solid (0.11 g, 56%): LC/MS (Table 2, Method a) R_(t)=1.53 min; MSm/z 387 (M+H)⁺.

Example #8 7-Cyclohexyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine

Step A: tert-Butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate

To a flask was added Pd₂(dba)₃ (1.3 g, 1.42 mmol),di-tert-butyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (1.21 g,2.84 mmol), and 1,4-dioxane (75 mL). The catalyst-ligand mixture wasdegassed via vacuum/nitrogen purge (3 times) and heated at about 80° C.for about 10 min. Then 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (5.0 g,14.2 mmol, Preparation #7), tert-butyl carbamate (2.5 g, 21.29 mmol),and NaOt-Bu (2.05 g, 21.29 mmol) were added. After an additionalvacuum/nitrogen purge, the reaction was heated at about 80° C. for about16 h. The reaction was cooled to ambient temperature and diluted withEtOAc (70 mL). The reaction mixture was filtered and the filtrate waswashed with water (3×20 mL). The organic layer was dried over anhydrousMgSO₄, filtered, and solvent removed under reduced pressure to give areddish-brown solid. The crude material was purified via silica gelchromatography eluting with a gradient of 10-50% EtOAc in heptane toyield tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate as ayellow amorphous solid (1.0 g, 18%): LC/MS (Table 2, Method a)R_(t)=2.63 min; MS m/z: 389 (M+H)⁺.

Step B: 5-Tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine hydrochloride

tert-Butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (1.00 g, 2.57mmol) was subjected to General Procedure I to afford5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine hydrochloride (0.40 g, 54%):LC/MS (Table 2, Method a) R_(t)=1.94 min; MS m/z: 289 (M+H)⁺.

Step C: 7-Cyclohexyl-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine

To a suspension of 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-aminehydrochloride (0.10 g, 0.35 mmol) and 2-bromo-1-cyclohexylethanone(0.078 g, 0.38 mmol, 3B Pharmachem) in n-BuOH (1.5 mL) was added DIEA(0.067 g, 0.52 mmol) and the resulting solution was heated at about 170°C. in the CEM™ microwave for about 30 min. The solvent was removed underreduced pressure to afford7-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine as a crudesolid that was used in Step D without further purification: LC/MS (Table2, Method a) R_(t)=2.71 min; MS m/z: 395 (M+H)⁺.

Step D: 7-Cyclohexyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine

7-Cyclohexyl-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.13 g,0.33 mmol) was dissolved in 1,4-dioxane (5 mL) and aqueous NaOH (2N, 0.5mL) was added. The mixture was heated at reflux for about 30 min. Theorganic solvent was removed under reduced pressure. The aqueous phasewas neutralized with 1 N aqueous HCl and extracted with EtOAc (2×25 mL).The combined organic extracts were washed with brine (15 mL), dried overanhydrous MgSO₄, and concentrated under reduced pressure. The residuewas purified by RP-HPLC (Table 2, Method h) to yield7-cyclohexyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine as an off-whitesolid (0.011 g, 14%): LC/MS (Table 2, Method a) R_(t)=2.06 min; MS m/z:241 (M+H)⁺.

Example #9 8-Cyclohexyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine

Step A: tert-Butyl2-cyclohexyl-2-oxoethyl-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate

NaH (60% in mineral oil, 0.020 g, 0.49 mmol) was added to dry DMF (3mL). The suspension was cooled to about 0° C. and a solution oftert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.19 g, 0.489mmol, Example #8, Step A) in dry DMF (2 mL) was added drop-wise. Thereaction mixture was allowed to warm to ambient temperature and2-bromo-1-cyclohexylethanone (0.10 g, 0.49 mmol, 3B PharmaChem) wasadded. The reaction mixture was stirred for about 2 h and thenconcentrated under reduced pressure. Purification by silica gel flashchromatography eluting with 100% heptane for 10 min and a gradient of10-20% EtOAc in heptane over 20 min yielded tert-butyl2-cyclohexyl-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamateas a yellow amorphous solid (0.080 g, 32%): LC/MS (Table 2, Method a)R_(t)=3.13 min; MS m/z: 513 (M+H)⁺.

Step B: 8-Cyclohexyl-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine

Concentrated H₂SO₄ (4 mL) was added to tert-butyl2-cyclohexyl-2-oxoethyl-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate(0.07 g, 0.14 mmol) and the reaction mixture was stirred for about 30min at ambient temperature. The reaction mixture was poured ontoice-cold water (75 mL) and extracted with EtOAc (2×50 mL). The combinedorganic extracts were washed with brine, dried over anhydrous MgSO₄, andconcentrated to yield8-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine as a yellowoil that was used in Example #9, Step C without further purification(0.051 g, 95%): LC/MS (Table 2, Method a) R_(t)=2.79 min; MS m/z: 395(M+H)⁺.

Step C: 8-Cyclohexyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine

Aqueous NaOH (2N, 0.3 mL) was added to8-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.051 g,0.13 mmol) in 1,4-dioxane (3 mL) and the mixture was heated at refluxfor about 1 h. The organic solvent was removed under reduced pressureand the aqueous phase neutralized with aqueous 1 N HCl and extractedwith EtOAc (2×15 mL). The combined organic extracts were washed withbrine (1×10 mL), dried over anhydrous MgSO₄, and concentrated in vacuo.The residue was suspended in MeCN (2 mL) and the precipitate wascollected by filtration and dried to yield8-cyclohexyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine as a tan solid(0.006 g, 19%): LC/MS (Table 2, Method a) R_(t)=2.12 min; MS m/z: 241(M+H)⁺.

Example #10 1-Cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine

Step A: (E)-2-Styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (3.1 g, 8.8mmol, Preparation #7), PdCl₂(dppf).DCM (0.719 g, 0.880 mmol) and(E)-styrylboronic acid (2.60 g, 17.6 mmol) in THF (3 mL) and water (2mL) was added Na₂CO₃ (2.33 g, 22.0 mmol). The reaction mixture wasdegassed with argon for about 5 min. The reaction mixture was heated toabout 50° C. After about 24 h, additional PdCl₂(dppf).DCM (0.719 g,0.880 mmol), (E)-styrylboronic acid (2.60 g, 17.6 mmol) and Na₂CO₃ (2.33g, 22.0 mmol) were added to the reaction mixture. After heating at about50° C. for about 48 h, the reaction mixture was cooled to ambienttemperature and diluted with DCM (200 mL) and water (200 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. Purification by chromatography oversilica gel eluting with a gradient of 20-60% EtOAc in heptane containing5% DCM provided (E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as ayellow solid (1.2 g, 36%). LC/MS (Table 2, Method a) R_(t)=2.99 min; MSm/z: 376 (M+H)⁺.

Step B: 5-Tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde

To a solution of (E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (1.2 g,3.2 mmol) in 1,4-dioxane (20 mL) and water (2.0 mL) was added sodiumperiodate (2.73 g, 12.8 mmol) followed by osmium tetroxide (2.5% int-BuOH, 4.01 mL, 0.320 mmol). After about 1 day at ambient temperature,additional sodium periodate (2.73 g, 12.78 mmol) and osmium tetroxide(2.5% in t-BuOH, 4.01 mL, 0.320 mmol) were added. After about 2 days, asolution of aqueous Na₂S₂O₃ (100 mL) and EtOAc (100 mL) was added. Theorganic layer was separated, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The resulting solid was trituratedwith heptane to remove benzaldehyde. The resulting solid was dried invacuo to provide 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde as abrown solid (0.77 g, 80%): LC/MS (Table 2, Method a) R_(t)=2.01 min; MSm/z: 334 (M+H)⁺.

Step C:N-((5-Tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide

To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (0.150g, 0.498 mmol) in MeOH (10 mL) was added hydroxylamine (50% solution inwater, 0.061 mL, 1.0 mmol). The reaction mixture was heated to about 45°C. After about 2 h, the reaction mixture was cooled to ambienttemperature and concentrated under reduced pressure to provide the crude5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde oxime as a tan solid.LC/MS (Table 2, Method a) R_(t)=2.15 min; MS m/z: 317 (M+H)⁺. To asolution of the crude oxime in THF (20 mL) was added AcOH (0.285 mL,4.98 mmol) followed by zinc dust (<10 micron, 0.130 g, 1.99 mmol). Aftera further 2 h, additional AcOH (0.285 mL, 4.98 mmol) and zinc dust (<10micron, 0.130 g, 1.99 mmol) were added to the reaction mixture. Afterabout an additional 2 h, additional AcOH (0.285 mL, 4.98 mmol) and zincdust (<10 micron, 0.130 g, 1.99 mmol) were added to the reactionmixture. After about 15 h, the reaction mixture was diluted with DCM(about 5 mL) and filtered. The filtrate was washed with saturatedaqueous NaHCO₃ and brine. The organic layer was dried over anhydrousNa₂SO₄, filtered, treated with HCl (4 M in 1,4-dioxane, 1 mL) andconcentrated under reduced pressure to provide(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride: LC/MS(Table 2, Method a) R_(t)=1.64 min; MS m/z: 303 (M+H)⁺. To a suspensionof the crude amine hydrochloride in DCM (10 mL) was added TEA (0.208 mL,1.49 mmol) followed by cyclohexanecarbonyl chloride (0.101 mL, 0.747mmol). After about 30 min, the reaction mixture was diluted with DCM andwashed with saturated aqueous NaHCO₃ (25 mL) and brine (25 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude amide was purified bysilica gel chromatography eluting with a gradient of 40-80% EtOAc in DCMto provideN-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamideas a tan solid (0.081 g, 39% over 2 steps). LC/MS (Table 2, Method a)R_(t)=2.40 min; MS m/z: 413 (M+H)⁺.

Step D: 1-Cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine

To a solution ofN-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide(0.081 g, 0.196 mmol) in THF (1 mL) at ambient temperature was added2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(0.104 g, 0.196 mmol, TCI). After about 15 h, the reaction mixture wasconcentrated under reduced pressure. The residue was suspended inEtOAc/DCM (1:1) and filtered through a plug of silica gel (5 g) elutingwith EtOAc/DCM (1:1, approximately 100 mL). Concentration of thefiltrate provided the crudeN-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarbothioamide.The crude thioamide was dissolved in THF (1 mL) and diacetoxymercury(0.0626 g, 0.196 mmol) was added. After about 30 min at ambienttemperature, additional diacetoxymercury (0.0626 g, 0.196 mmol) wasadded. After about 4 h, the reaction mixture was diluted with EtOAc,filtered, concentrated under reduced pressure, and purified by silicagel chromatography eluting with a gradient of 50-95% EtOAc in heptane toprovide 1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine asa yellow oil (0.020 g, 25%): LC/MS (Table 2, Method a) R_(t)=2.77 min;MS m/z: 395 (M+H)⁺.

Step E: 1-Cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine

To a solution of1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.020 g,0.051 mmol) in 1,4-dioxane (3 mL) was added aqueous NaOH (2 N, 0.380 mL,0.760 mmol). The reaction mixture was heated to about 90° C. After about5 h, the reaction mixture was cooled to ambient temperature and dilutedwith EtOAc (10 mL) and saturated aqueous NH₄Cl (10 mL). The organiclayer was separated and washed with water (10 mL) followed by brine (10mL), dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure to provide1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine as a tan solid(0.011 g, 90%): LC/MS (Table 2, Method a) R_(t)=1.92 min; MS m/z: 241(M+H)⁺.

Example #11 8-Cyclohexyl-3H-dipyrrolo[1,2-a:2′,3′-e]pyrazine

Step A:(E)-1-Cyclohexyl-3-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)prop-2-en-1-one

To a solution of diethyl 2-cyclohexyl-2-oxoethylphosphonate (0.609 g,2.32 mmol) in THF (10 mL) was added NaH (60% dispersion in mineral oil,0.0664 g, 1.66 mmol). After about 30 min, a solution of5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (0.20 g, 0.64 mmol,Example #10, Step B) in THF (10 mL) was added. After about 2 h, EtOAc(50 mL) and saturated aqueous NH₄Cl (50 mL) was added to the reactionmixture. The organic layer was separated, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The residue wastriturated with IPA (20 mL) to provide(E)-1-cyclohexyl-3-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)prop-2-en-1-oneas a tan solid (0.20 g, 73%): LC/MS (Table 2, Method a) R_(t)=3.06 min;MS m/z: 410 (M+H)⁺.

Step B:1-Cyclohexyl-3-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)propan-1-one

To a solution of(E)-1-cyclohexyl-3-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)prop-2-en-1-one(0.050 g, 0.12 mmol) in EtOAc (5 mL) was added palladium (10% on carbon,0.0065 g, 0.0061 mmol). The reaction mixture was purged with hydrogenand a hydrogen atmosphere was maintained via balloon. After about 1 h atambient temperature, the reaction mixture was filtered and concentratedunder reduced pressure to provide1-cyclohexyl-3-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)propan-1-one as anoil (0.050 g, 100%): LC/MS (Table 2, Method a) R_(t)=2.94 min; MS m/z:412 (M+H)⁺.

Step C: 8-Cyclohexyl-3-tosyl-3H-dipyrrolo[1,2-a:2′,3′-e]pyrazine

To a solution of1-cyclohexyl-3-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)propan-1-one(0.050 g, 0.12 mmol) in THF (2 mL) was added2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(0.071 g, 0.13 mmol, TCI). After about 6 h at ambient temperature, thereaction mixture was diluted with EtOAc (50 mL) and NaHCO₃ (50 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude product was purified bychromatography on silica gel eluting with a gradient of 40-90% EtOAc inheptanes to provide8-cyclohexyl-3-tosyl-3H-dipyrrolo[1,2-a:2′,3′-e]pyrazine as a tan solid(0.020 g, 42%). LC/MS (Table 2, Method a) R_(t)=3.39 min; MS m/z: 394(M+H)⁺.

Step D: 8-Cyclohexyl-3H-dipyrrolo[1,2-a:2′,3′-e]pyrazine

To a solution of8-cyclohexyl-3-tosyl-3H-dipyrrolo[1,2-a:2′,3′-e]pyrazine (0.015 g, 0.038mmol) in 1,4-dioxane (3 mL) was added aqueous NaOH (2 N, 0.29 mL, 0.57mmol). The reaction mixture was heated to about 90° C. After about 15 h,the reaction mixture was cooled to ambient temperature and diluted withEtOAc (5 mL) and saturated aqueous NH₄Cl (5 mL). The organic layer wasseparated, washed with water (5 mL) followed by brine (5 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was triturated with EtOAc/heptane (1:1, 1 mL). The resultingsolid was collected by filtration and dried in vacuo to provide8-cyclohexyl-3H-dipyrrolo[1,2-a:2,3′-e]pyrazine as a tan solid (0.005 g,55%). LC/MS (Table 2, Method a) R_(t)=2.78 min; MS m/z: 240 (M+H)⁺.

Example #12N-(4-(6H-Imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide

Step A: tert-Butyl4-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)bicyclo[2.2.2]octan-1-ylcarbamate

To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (0.49g, 1.6 mmol, Example #10, Step B) in MeOH (10 mL) was addedhydroxylamine (50% in water, 0.199 mL, 3.25 mmol). The reaction mixturewas heated to about 40° C. After about 2 h, the reaction mixture wascooled to ambient temperature and concentrated under reduced pressure.To a solution of the crude oxime in THF (10 mL) and AcOH (0.93 mL, 16mmol) was added zinc dust (<10 micron, 0.425 g, 6.50 mmol). After about4 h at ambient temperature, the reaction mixture was diluted with DCMand saturated aqueous NaHCO₃ and filtered through Celite®. The layerswere separated and the organic layer was dried over anhydrous Na₂SO₄,filtered, treated with HCl (4 N in 1,4-dioxane, 1 mL) and concentratedunder reduced pressure. To a solution of the crude amine in DCM (10 mL)was added 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylicacid (0.48 g, 1.8 mmol, Prime Organics), TEA (0.23 mL, 1.6 mmol) andHATU (0.618 g, 1.63 mmol). After about 4 h at ambient temperature, thereaction mixture was diluted with DCM and saturated aqueous NaHCO₃ andfiltered through Celite®. The layers were separated and the organiclayer was dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. The crude amide was purified by chromatography onsilica gel eluting with a gradient of 20-80% EtOAc in DCM to providetert-butyl-4-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)bicyclo[2.2.2]octan-1-ylcarbamateas a tan solid (0.205 g, 23%). LC/MS (Table 2, Method a) R_(t)=2.52 min;MS m/z: 554 (M+H)⁺.

Step B: tert-Butyl4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamate

To a solution of tert-butyl4-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)-bicyclo[2.2.2]octan-1-ylcarbamate(0.205 g, 0.370 mmol) in THF (5 mL) was added2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(0.215 g, 0.407 mmol, TCI America). After about 15 h at ambienttemperature, diacetoxymercury (0.295 g, 0.926 mmol) was added to thereaction mixture. After about 2 h, the reaction mixture was diluted withEtOAc (30 mL) and filtered through Celite®. The filtrate wasconcentrated under reduced pressure and the crude mixture was purifiedby chromatography on silica gel eluting with a gradient of 20-80% EtOAcin DCM to provide tert-butyl4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamateas a tan solid (0.175 g, 84%). LC/MS (Table 2, Method a) R_(t)=2.84 min;MS m/z: 536 (M+H)⁺.

Step C:N-(4-(6-Tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide

To a flask containing tert-butyl4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamate(0.175 g, 0.327 mmol) was added a solution of HCl (4 N in 1,4-dioxane, 5mL). After about 2 h at ambient temperature, the reaction mixture wasconcentrated under reduced pressure. The crude amine hydrochloride wasdissolved in DCM (10 mL) and TEA (0.36 mL, 2.6 mmol) was added to thereaction mixture followed by cyclopropanesulfonyl chloride (0.18 g, 1.3mmol). After about 2 h at ambient temperature, DMF (3 mL) was added andthe reaction mixture was concentrated under reduced pressure to removeDCM. After a further about 4 h at ambient temperature, EtOAc (20 mL) andsaturated aqueous NaHCO₃ (20 mL) was added to the reaction mixture. Theorganic layer was separated, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude reaction mixture waspurified by chromatography on silica gel using 20-80% EtOAc in DCM toprovideN-(4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamideas a tan solid (0.025 g, 14%). LC/MS (Table 2, Method a) R_(t)=2.34 min;MS m/z: 540 (M+H)⁺.

Step D:N-(4-(6H-Imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide

To a solution ofN-(4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide(0.025 g, 0.046 mmol) in 1,4-dioxane (3 mL) was added aqueous NaOH (2 N,0.35 mL, 0.70 mmol). The reaction mixture was heated to about 90° C.After about 6 h, the reaction mixture was cooled to ambient temperatureand EtOAc (3 mL) and saturated aqueous NH₄Cl (1.5 mL) was added. Thelayers were separated and the organic layer was washed with water (1.5mL) followed by brine (1.5 mL), dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure to provideN-(4-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamideas a tan solid (0.012 g, 67%). LC/MS (Table 2, Method a) R_(t)=1.65 min;MS m/z: 386 (M+H)⁺.

Example #133-((3R,4R)-3-(6H-Imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-3-oxopropanenitrile

Step A: 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (78.0 g, 394 mmol, ArkPharm) in anhydrous DMF (272 mL) was added drop-wise over about 60 minto a stirred suspension of NaH (60% dispersion in mineral oil, 12.8 g,532 mmol) in anhydrous DMF (543 mL) at about 0-5° C. The brown reactionsolution was stirred for about 30 min at about 0-5° C. then a solutionof p-toluenesulfonyl chloride (94.0 g, 492 mmol) in anhydrous DMF (272mL) was added drop-wise over about 60 min at about 0-5° C. The reactionmixture was stirred at about 0-5° C. for about 1 h then allowed to warmto ambient temperature and stirred for about 18 h at ambienttemperature. The reaction mixture was poured slowly into ice water (6L), followed by the addition of aqueous NaOH (2.5M, 50.0 mL, 125 mmol).The precipitate was collected by filtration and stirred with cold water(3×200 mL). The solid was collected by filtration and dried to constantweight in a vacuum oven at about 55° C. to yield2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine: (134.6 g, 97%) as a palebeige solid: LC/MS (Table 2, Method d) R_(t)=1.58 min; MS m/z: 352/354(M+H)⁺.

Step B: (E)-2-Styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (75 g, 213mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (8.69 g, 10.6 mmol) and(E)-styrylboronic acid (39.4 g, 266 mmol) in THF (600 mL) was addedNa₂CO₃ (27.1 g, 256 mmol) and water (300 mL). The reaction mixture wasdegassed with nitrogen for about 45 min. The reaction mixture was heatedto about 65° C. for about 16 h then PdCl₂ (dppf)-CH₂Cl₂ adduct (3.50 g,4.29 mmol) was added. After about 18 h, the reaction was cooled toambient temperature. The layers were separated and the organic layer wasconcentrated under reduced pressure. The residue was triturated in EtOH(300 mL)/DCM (100 mL) and filtered. The precipitate was triturated inhot EtOH (400 mL) and filtered, then washed with EtOH (200 mL) and Et₂O(400 mL). The filtrates were recombined, concentrated under reducedpressure, and the resulting residue was triturated in EtOH (300 mL)/DCM(100 mL) and stirred overnight while allowing the DCM to slowlyevaporate. The mixture was filtered and washed with EtOH (100 mL) andEt₂O (100 mL) to give a second crop. The combined filter cakes weredried under vacuum to provide(E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (72.7 g, 91%) as a tansolid: LC/MS (Table 2, Method a) R_(t)=2.66 min; MS m/z: 376 (M+H)⁺.

Step C: 5-Tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde

To a solution of (E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (72.3 g,193 mmol) in 1,4-dioxane (1500 mL) and water (300 mL) was added NaIO₄(165 g, 770 mmol) followed by OSO₄ (5.00 g, 19.7 mmol). The reaction wasstirred at about 25° C. for about 16 h. The reaction was concentratedunder reduced pressure then was partitioned with 10% aqueous Na₂S₂O₃(1000 mL) and DCM (1000 mL). The organic layer was washed with water(2×500 mL) and the layers were filtered to remove undissolvedprecipitate and separated. The organic layer was dried over anhydrousNa₂SO₄, filtered through Celite®, and concentrated. The residue waspurified by filtration through a pad of silica gel (1000 g) eluting with0-5% EtOAc in DCM. The fractions were concentrated and the solid wastriturated with heptane. The mixture was filtered and the filter cakewas washed with heptane. This procedure was repeated for the collectedundissolved precipitate. The collected solid was then dissolved in 2%EtOAc in DCM and passed through a pad of silica gel (100 g) eluting with2% EtOAc in DCM. The filtrate was concentrated under reduced pressure.The two batches were combined to give5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (39.1 g, 67%) as anoff-white solid: LC/MS (Table 2, Method a) R_(t)=2.17 min; MS m/z: 302(M+H)⁺.

Step D: (5-Tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol

To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (37.6g, 125 mmol) in EtOH (500 mL) and 1,4-dioxane (500 mL) was added NaBH₄(4.72 g, 125 mmol) in one portion. After about 3 h, aqueous HCl (1N, 400mL) was slowly added to the reaction mixture. The mixture wasconcentrated to one-half the original volume under reduced pressure andEtOAc (1000 mL) and water (500 mL) were added to the mixture. The layerswere separated and the aqueous layer was extracted with EtOAc (500 mL).The combined organic layers were dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure to provide(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol (35.9 g, 95% yield) as atan solid: LC/MS (Table 2, Method a) R_(t)=1.97 min; MS m/z: 304 (M+H)⁺.

Step E: 2-(Azidomethyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a solution of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol (35.8g, 118 mmol) in DCM (600 mL) was added SOCl₂ (21.5 mL, 295 mmol). Afterabout 4 h at ambient temperature, additional SOCl₂ (8.60 mL, 118 mmol)was added. After about 16 h, the reaction was concentrated under reducedpressure and washed with saturated aqueous NaHCO₃ (1000 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. The resulting residue was dissolved in DCM (600 mL)and re-subjected to SOCl₂ (21.51 mL, 295 mmol). After about 16 h atambient temperature, the reaction was concentrated under reducedpressure followed by the addition of DCM (500 mL) and saturated aqueousNaHCO₃ (500 mL). The layers were separated and the organic layer wasdried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. To the resulting residue was added DMF (500 mL) followed byNaN₃ (38.3 g, 589 mmol). After about 16 h, at ambient temperature EtOAc(500 mL) was added and the organic solution was washed with water:brine(1:1, 2000 mL). The layers were separated and the aqueous layer wasfurther extracted with EtOAc (500 mL). The combined organic layers werewashed with brine (3×1000 mL), dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure to provide2-(azidomethyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (32.65 g, 82% yield)as a tan solid: LC/MS (Table 2, Method a) R_(t)=2.31 min; MS m/z: 329(M+H)⁺.

Step F: (5-Tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride

To a solution of 2-(azidomethyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (32.6g, 99.0 mmol) in THF (100 mL) and water (50 mL) was added Ph₃P (31.3 g,119 mmol). The reaction mixture was heated to about 45° C. for about 16h. The mixture was allowed to cool to ambient temperature followed byremoval of THF under reduced pressure. The mixture was partitionedbetween EtOAc (500 mL) and brine (250 mL), dried over anhydrous Na₂SO₄,and filtered. The filtrate was diluted with EtOAc to IL total volume. Tothe rapidly stirring solution was added drop-wise 4N HCl (4N in dioxane,30.0 mL, 120 mmol) resulting in formation of a tan precipitate. MeOH (10mL) was added and the mixture was filtered after about 15 min. Theprecipitate was triturated with Et₂O (1000 mL) for about 10 min,filtered, and washed with Et₂O (500 mL) to provide(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (32.0g, 90%) as a tan solid: LC/MS (Table 2, Method a) R_(t)=1.44 min; MSm/z: 303 (M+H)⁺.

Step G: 1-(tert-Butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid

4-Methylnicotinic acid hydrochloride (5.00 g, 36.5 mmol, ASDI) andplatinum (IV) oxide (0.35 g, 1.54 mmol) were shaken in AcOH (100 mL) atabout 60 psi hydrogen for about 72 h. The reaction mixture was filteredthrough Celite® and concentrated under reduced pressure to give4-methylpiperidine-3-carboxylic acid hydrochloride (7.4 g, containedresidual AcOH) that was carried forward without additional purification.To a solution of the acid (7.40 g, 36.4 mmol) and NaHCO₃ (15.3 g, 182mmol) in MeCN (75 mL) and water (125 mL) was added Boc₂O (11.0 mL, 47.3mmol). The reaction was stirred at about 25° C. for about 16 h. Thereaction mixture was diluted with Et₂O (100 mL) and acidified to pH 1with 4N aqueous HCl. The layers were separated and the organic solutionwas washed with brine (2×100 mL), dried over anhydrous Na₂SO₄, filtered,and concentrated. A white solid formed that was triturated with heptaneand collected by vacuum filtration to give1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (5.2 g, 58%over 2 steps): LC/MS (Table 2, Method a) R_(t)=2.01 min; MS m/z: 242(M−H)⁻.

Step H: tert-Butyl4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate

To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanaminehydrochloride (29.6 g, 87.0 mmol, Step F),1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (21.2 g,87.0 mmol, Step G) and HATU (33.2 g, 87.0 mmol) in DCM (400 mL) wasadded DIEA (46.0 mL, 263 mmol). After stirring for about 18 h at ambienttemperature, the reaction mixture was washed with aqueous saturatedNaHCO₃ (400 mL). The organic layer was separated, dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (330 g column) eluting with agradient of 50-100% EtOAc in heptane to give tert-butyl4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate(44 g, 95%) as a tan foam: LC/MS (Table 2, Method a) R_(t)=2.38 min; MSm/z: 528 (M+H)⁺.

Step I: tert-Butyl4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate(44 g, 83 mmol) in 1,4-dioxane (500 mL) was added Lawesson's reagent(20.2 g, 50.0 mmol). The reaction was heated at about 80° C. for about 1h. The reaction was allowed to cool to ambient temperature followed bythe addition of diacetoxymercury (26.6 g, 83.0 mmol). After about 1 h,additional diacetoxymercury (13.3 g, 42.0 mmol) was added. After about15 min, the reaction was poured into stirred EtOAc (2 L). After about 15min, the reaction was filtered through Celite® and the filtrate wasconcentrated under reduced pressure. The resulting residue wastriturated with EtOAc (500 mL) and filtered. The filtrate wasconcentrated under reduced pressure and purified by silica gelchromatography (330 g column) eluting with a gradient of 10-50% EtOAc inheptane to provide tert-butyl4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(19 g, 44%) as a white solid: LC/MS (Table 2, Method a) R_(t)=2.57 min;MS m/z: 510 (M+H)⁺.

Step J: tert-Butyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate

To a solution of tert-butyl4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate(19.0 g, 37.3 mmol) in 1,4-dioxane (100 mL) was added aqueous NaOH (1N,74.6 mL, 74.6 mmol). The reaction was heated at about 60° C. for about30 min and allowed to cool to ambient temperature followed by theaddition of 10% aqueous AcOH (250 mL). The mixture was extracted withEtOAc (2×250 mL) and the combined organic layers were washed with brine(200 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate wasconcentrated under reduced pressure and purified by silica gelchromatography (330 g) eluting with a gradient of 10-70% EtOAc inheptane to provide tert-butyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate(12.3 g, 93%) as a white foam: LC/MS (Table 2, Method a) R_(t)=1.96 min;MS m/z: 356 (M+H)⁺.

Step K:1-(4-Methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride

To a solution of tert-butyl3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate(12.2 g, 34.3 mmol) in 1,4-dioxane (100 mL) was added 4N HCl (4N in1,4-dioxane, 25.7 mL, 103 mmol). The reaction mixture was heated atabout 60° C. for about 2 h. The mixture was allowed to cool to ambienttemperature and was diluted with Et₂O (100 mL). The mixture wastriturated and filtered, and the precipitate was washed with Et₂O (100mL) to give1-(4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (10 g, 98% yield) as a tan solid: LC/MS (Table 2, Methoda) R_(t)=1.05 min; MS m/z: 256 (M+H)⁺.

Step L:3-((3R,4R)-3-(6H-Imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-3-oxopropanenitrile

To a solution of1-((3)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinehydrochloride (10.0 g, 34.3 mmol), DIEA (23.9 mL, 137 mmol) and2-cyanoacetic acid (4.37 g, 51.4 mmol) in DMF (100 mL) was added EDC(7.88 g, 41.1 mmol). The reaction mixture was stirred at about 25° C.for about 16 h. Additional EDC (7.88 g, 41.1 mmol) was added and afterabout 5 h, the reaction was quenched with water (30 mL) and concentratedunder reduced pressure. The residue was partitioned between DCM (2×500mL) and brine (500 mL). The combined organic layers were dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated underreduced pressure and purified by silica gel chromatography (120 gcolumn) eluting with a gradient of 0-10% MeOH in DCM followed by chiralchromatography to give3-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-3-oxopropanenitrile[Table 3, Method 9, R_(t) 14.5 min, or =positive] (2.1 g, 24%) as anoff-white solid: LC/MS (Table 2, Method a) R_(t)=1.05 min; MS m/z: 256(M+H)⁺.

Example #14N-((1S,3R,4S)-3-Methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide

Step A: Sodium4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate

A round bottom flask was charged with THF (1 L) followed by theportion-wise addition of sodium hydride (60% dispersion in mineral oil,30.7 g, 0.77 mol). The resulting mixture was cooled to about −10° C. andethyl 3-oxobutanoate (97 mL, 0.77 mol) was added drop-wise over about 1h in order to keep the internal temperature below about 10° C. Theresulting mixture was stirred at ambient temperature for about 1 h togive a clear yellow solution, and methyl 4-chloroacetoacetate (44.3 mL,0.384 mol) was added drop-wise over about 5 min. The resulting mixturewas heated to about 50° C. for about 19 h to give a yellow-orangesuspension. The reaction mixture was then concentrated under reducedpressure and the resulting solid was transferred to a beaker and dilutedwith water (350 mL). The solid was collected by vacuum filtration andthe filter cake was rinsed with water (150 mL) and dried under vacuumfor about 1 h. The solid was suspended in Et₂O (500 mL), filtered,washed with Et₂O (500 mL), and dried under vacuum to give sodium4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate(77.4 g, 81%) as a beige solid: ¹H NMR (DMSO-d₆) δ 3.96 (q, J=7.1 Hz,2H), 3.33 (s, 3H), 2.72 (d, J=2.2 Hz, 2H), 2.47 (t, J=2.1 Hz, 3H), 1.15(t, J=7.1 Hz, 3H).

Step B: Ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate

A round-bottom flask was charged with sodium4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate(105 g, 0.420 mol) and diglyme (1 L) to give a yellow suspension. AcOH(100 mL, 1.7 mol) was added to the resulting mixture and sodium iodide(280 g, 1.9 mol) was added portion-wise over about 5-10 min. Thereaction mixture was then heated to reflux for about 3 h, cooled to roomtemperature, and poured over ice water (800 mL). The resulting materialwas extracted with Et₂O (3×500 mL). The combined organic extracts werewashed with brine (2×500 mL), dried over anhydrous MgSO₄, and filtered.The solvent was removed under reduced pressure to give a brown liquidthat was purified by vacuum distillation (80-85° C., 0.3 Torr) to giveethyl 2-methyl-4-oxocyclopent-2-enecarboxylate (40.6 g, 57%) as a yellowoil: ¹H NMR (CDCl₃) δ 6.06-5.98 (m, 1H), 4.30-4.11 (m, 2H), 3.72-3.65(m, 1H), 2.77-2.66 (m, 1H), 2.66-2.57 (m, 1H), 2.17 (s, 3H), 1.30 (t,J=7.1 Hz, 3H).

Step C: Ethyl 2-methyl-4-oxocyclopentanecarboxylate

A round-bottom flask was charged with 10% palladium on carbon (7.6 g,7.1 mmol). The flask was cooled to about 0° C. and EtOAc (580 mL) wasadded under a nitrogen atmosphere. The cooling bath was removed andethyl 2-methyl-4-oxocyclopent-2-enecarboxylate (60.0 g, 357 mmol) wasadded. Hydrogen gas was bubbled through the mixture for about 5 min andthe mixture was then stirred under a hydrogen atmosphere (1 atmosphere)for about 48 h. The hydrogen source was removed and the mixture wasbubbled with nitrogen for about 5 min and was filtered through a pad ofCelite®. The filter cake was rinsed with EtOAc (500 mL). The filtratewas concentrated under reduced pressure to give ethyl2-methyl-4-oxocyclopentanecarboxylate (59.9 g, 99%) as a yellow liquid:¹H NMR (CDCl₃) δ 4.23-4.14 (m, 2H), 3.18 (ddd, J=5.6, 6.8, 8.1 Hz, 1H),2.73-2.65 (m, 1H), 2.60 (ddd, J=1.7, 5.5, 18.7 Hz, 1H), 2.42-2.29 (m,2H), 2.15 (ddd, J=1.7, 7.9, 18.3 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H), 1.07(d, J=7.0 Hz, 3H).

Step D: Ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate

A round-bottom flask was charged with ethyl2-methyl-4-oxocyclopentanecarboxylate (10.0 g, 58.8 mmol) and DCE (180mL). The solution was cooled to about 0° C. and AcOH (5.7 mL, 100 mmol)and dibenzylamine (11.3 mL, 58.8 mmol) were added drop-wise, resultingin formation of a thick suspension. The reaction mixture was warmed toabout 10° C. and sodium triacetoxyborohydride (21.2 g, 100 mmol) wasadded portion-wise and the reaction mixture was stirred at roomtemperature for about 20 h. The reaction mixture was slowly poured intostirred saturated aqueous NaHCO₃ (300 mL) for about 20 min. The layerswere separated and the aqueous phase was extracted with DCM (3×100 mL).The combined organic extracts were washed with brine (2×100 mL), driedover anhydrous Na₂SO₄, and concentrated to dryness under reducedpressure. The crude yellow oil was purified via flash columnchromatography eluting with a gradient of 0-30% EtOAc in heptane. Thesolvent was removed under reduced pressure to give ethyl4-(dibenzylamino)-2-methylcyclopentanecarboxylate (15.5 g, 75%) ascolorless oil: ¹H NMR (pyridine-d₅) δ 7.53 (dd, J=0.9, 7.9 Hz, 4H),7.43-7.35 (m, 4H), 7.33-7.25 (m, 2H), 4.22-4.06 (m, 2H), 3.79 (d, J=14.2Hz, 2H), 3.70 (d, J=14.2 Hz, 2H), 3.34-3.22 (m, 1H), 2.76 (dd, J=7.9,16.6 Hz, 1H), 2.25-2.13 (m, 1H), 2.09-1.94 (m, 2H), 1.88-1.79 (m, 1H),1.52 (dd, J=10.5, 22.5 Hz, 1H), 1.16 (t, J=7.1 Hz, 3H), 0.98 (d, J=7.0Hz, 3H).

Step E: Ethyl 4-amino-2-methylcyclopentanecarboxylate

To a vessel containing a slurry of 20% wet Pd(OH)₂—C (5.00 g, 35.6 mmol)in EtOH (355 mL) was added ethyl4-(dibenzylamino)-2-methylcyclopentanecarboxylate (50.0 g, 142 mmol).The reaction was shaken for about 60 min at about 50° C. under about 30psi of H₂. The resulting mixture was filtered through a pad of Celite®and the filtrate was concentrated under reduced pressure to give ethyl4-amino-2-methylcyclopentanecarboxylate (23.5 g, 96%) as a yellow oil:¹H NMR (CDCl₃) δ 4.24-4.02 (m, 2H), 3.41-3.27 (m, 1H), 2.81 (dd, J=7.6,15.4 Hz, 1H), 2.36-2.20 (m, 1H), 2.21-2.02 (m, 4H), 1.81-1.69 (m, 1H),1.33-1.15 (m, 4H), 0.98 (d, J=7.0 Hz, 3H).

Step F: Ethyl4-(cyclopropanesulfonamido)-2-methylcyclopentanecarboxylate

A solution of ethyl 4-amino-2-methylcyclopentanecarboxylate (15.0 g,88.0 mmol) in DMF (210 mL) was cooled to about 0° C. in an ice bath. TEA(30.5 mL, 219 mmol) was added and stirring was continued at about 0° C.for about 15 min and then cyclopropanesulfonyl chloride (12.3 g, 88.0mmol, Matrix) was added drop-wise. The resulting solution was stirred atabout 0° C. for about 2 h. The ice bath was removed and the reactionmixture continued stirring at ambient temperature for about 3 h. Thereaction was concentrated under reduced pressure and EtOAc (200 mL) andwater (100 mL) were added. The layers were separated and the organiclayer was washed with saturated aqueous NaHCO₃ (60 mL) and brine (60mL), dried over anhydrous MgSO₄, filtered, and concentrated underreduced pressure to give a reddish brown oil. The crude material waspurified by silica gel chromatography eluting with a gradient of 10-30%EtOAc in heptane to give ethyl4-(cyclopropanesulfonamido)-2-methylcyclopentanecarboxylate (21.3 g,88%) as a yellow oil: ¹H NMR (CDCl₃) δ 5.25 (d, J=9.9 Hz, 1H), 4.23-4.06(m, 2H), 4.03-3.90 (m, 1H), 2.80 (td, J=3.1, 7.5 Hz, 1H), 2.46-2.30 (m,2H), 2.29-2.14 (m, 2H), 1.97 (ddd, J=3.2, 4.2, 14.2 Hz, 1H), 1.42 (ddd,J=7.5, 11.5, 13.1 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H), 1.20-1.14 (m, 2H),1.02 (d, J=6.9 Hz, 3H), 1.00-0.96 (m, 2H).

Step G: 4-(Cyclopropanesulfonamido)-2-methylcyclopentanecarboxylic acid

To a flask containing ethyl4-(cyclopropanesulfonamido)-2-methylcyclopentanecarboxylate (7.5 g, 27.3mmol) was added aqueous NaOH (1N, 150 mL, 150 mmol). After stirring atambient temperature for about 5 h, the reaction was acidified to aboutpH 1 with aqueous 6 N HCl and extracted with DCM (3×100 mL). Thecombined organic layers were washed with brine, dried over anhydrousMgSO₄, filtered, and concentrated under reduced pressure to give crude4-(cyclopropanesulfonamido)-2-methylcyclopentanecarboxylic acidcontaining about 5 mol % DCM (6.6 g, 97%) as a white solid: ¹H NMR(DMSO-d₆) δ 12.09 (s, 1H), 7.11 (d, J=8.1 Hz, 1H), 3.66-3.53 (m, 1H),2.78-2.68 (m, 1H), 2.50 (tq, J=5.1, 7.7 Hz, 1H), 2.29-2.17 (m, 1H),2.17-2.01 (m, 2H), 1.82 (dt, J=9.9, 12.7 Hz, 1H), 1.24 (dt, J=8.9, 12.4Hz, 1H), 0.98-0.85 (m, 7H).

Step H: 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (78.0 g, 394 mmol, ArkPharm) in anhydrous DMF (272 mL) was added drop-wise over about 60 minto a stirred suspension of NaH (60% dispersion in mineral oil, 12.8 g,532 mmol) in anhydrous DMF (543 mL) at about 0-5° C. The brown reactionsolution was stirred for about 30 min at about 0-5° C. then a solutionof p-toluenesulfonyl chloride (94.0 g, 492 mmol) in anhydrous DMF (272mL) was added drop-wise over about 60 min at about 0-5° C. The reactionmixture was stirred at about 0-5° C. for about 1 h then allowed to warmto ambient temperature and stirred for about 18 h at ambienttemperature. The reaction mixture was poured slowly into ice water (6L), followed by the addition of aqueous NaOH (2.5M, 50.0 mL, 125 mmol).The precipitate was collected by filtration and stirred with cold water(3×200 mL). The solid was collected by filtration and dried to constantweight in a vacuum oven at about 55° C. to yield2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (134.6 g, 97%) as a pale beigesolid: LC/MS (Table 2, Method d) R_(t)=1.58 min; MS m/z: 352/354 (M+H)⁺.

Step I: tert-Butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate

To a flask was added Pd₂(dba)₃ (3.90 g, 4.26 mmol),di-tert-butyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (3.62 g,8.52 mmol), and anhydrous 1,4-dioxane (453 mL). The catalyst-ligandmixture was degassed via vacuum/nitrogen purge (3 times) and heated atabout 80° C. for about 10 min. Then2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0 g, 85 mmol), tert-butylhydrazinecarboxylate (16.9 g, 128 mmol), and NaOt-Bu (12.3 g, 128 mmol)were added. After an additional vacuum/nitrogen purge, the reaction washeated at about 80° C. After about 50 min, the reaction mixture wascooled to ambient temperature and filtered through a pad of silica geltopped with Celite® while washing with EtOAc (3×150 mL). Water (300 mL)was added to the filtrate and the organic layer was separated. Theaqueous layer was extracted with additional EtOAc (3×200 mL). Thecombined organic extracts were washed with saturated aqueous NH₄Cl,saturated aqueous NaHCO₃, and brine (400 mL each), dried over anhydrousMgSO₄, filtered, and concentrated under reduced pressure to give a darkbrown oil (45 g). The brown oil was dissolved in DCM (250 mL), silicagel (200 g) was added, and the mixture was concentrated under reducedpressure. The resulting silica mixture was purified using silica gelchromatography eluting with a gradient of 25-65% EtOAc in heptane togive a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [majorregioisomer] and tert-butyl1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [minorregioisomer] (18.8 g, 50%): LC/MS (Table 2, Method d) R_(t)=1.47 min; MSm/z: 404 (M+H)⁺.

Step J: 2-Hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(18.8 g, 46.6 mmol) in 1,4-dioxane (239 mL) was added HCl (4 M in1,4-dioxane, 86 mL, 345 mmol). The reaction was heated at about 60° C.for about 1 h and then cooled to about 15-20° C. The solid was collectedby vacuum filtration, washed with cold 1,4-dioxane (2×20 mL), and thenstirred with a solution of saturated aqueous NaHCO₃ and water (1:1, 150mL). After about 1 h, the effervescence had subsided and the solid wascollected by vacuum filtration, washed with ice cold water (3×20 mL),and dried in a vacuum oven to a constant weight to afford2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a light yellowishbrown solid (8.01 g, 50%): LC/MS (Table 2, Method d) R_(t)=1.28 min; MSm/z: 304 (M+H)⁺.

Step K:N-(3-Methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide

To a solution of4-(cyclopropanesulfonamido)-2-methylcyclopentanecarboxylic acid (15.3 g,61.8 mmol, Step G) in DCM (300 mL) was added2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (18.3 g, 57.2 mmol, StepJ), HATU (22.9 g, 60.1 mmol) and TEA (32.0 mL, 229 mmol). After stirringat ambient temperature for about 1 h, the reaction was diluted withwater (250 mL). The layers were separated and the aqueous layer wasextracted with DCM (2×200 mL). The combined organic layers were washedwith brine, dried over anhydrous MgSO₄, filtered, and concentrated underreduced pressure. The crude material was diluted with DCM, forming athick suspension. Heptane was added to the suspension which was filteredto give an off-white solid. Silica gel (25 g) was added to the filtrateand the mixture was concentrated under reduced pressure. The resultingsilica mixture was purified using silica gel chromatography eluting witha gradient of 60-100% EtOAc in heptane. The product-containing fractionswere combined and concentrated under reduced pressure. The resulting tansolid was added to the previously collected precipitate and dried on avacuum pump for about 14 h to give impureN-(3-methyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)cyclopropanesulfonamide(25.2 g) contaminated with about 50 mol % tetramethylurea. To a solutionof impureN-(3-methyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)cyclopropanesulfonamide(25.2 g, 47.4 mmol) in 1,4-dioxane (395 mL) was added TEA (26.5 mL, 189mmol) and thionyl chloride (3.5 mL, 48 mmol). The reaction was heated atabout 80° C. for about 1.5 h, at which point the reaction mixture hadsolidified. The reaction was cooled to ambient temperature and the solidwas dissolved in DCM (1 L). The organics were washed with water (2×500mL) and brine (2×500 mL), dried over MgSO₄, filtered, and concentratedby half under reduced pressure. Silica gel (75 g) was added and theremainder of the solvent was removed under reduced pressure. Theresulting mixture was purified using silica gel chromatography elutingwith a gradient of 0-50% acetone in DCM. The product-containingfractions were combined and concentrated under reduced pressure, duringwhich time a thick gel was formed which subsequently solidified to giveN-(3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide(18.1 g, 62%) as a light brown solid: LC/MS (Table 2, Method a)R_(t)=2.16 min; MS m/z: 515 (M+H)⁺.

Step L:N-((1S,3R,4S)-3-Methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide

A mixture ofN-(3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide(7.1 g, 13.9 mmol), 1,4-dioxane (139 mL) and aqueous 1 N NaOH (30.0 mL,30.0 mmol) was heated at about 60° C. for about 2 h. The reaction wascooled to ambient temperature, diluted with water (150 mL), andextracted with EtOAc (3×150 mL). The combined organic layers were washedwith brine (200 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude mixture was trituratedwith EtOAc (50 mL) and filtered to give a tan solid, which was purifiedby chiral preparative HPLC (Table 3, Method 3, R_(t)=18 min, or=negative). The product containing fractions were combined andconcentrated to give a pale yellow solid. The solid was dissolved in a1:1 mixture of DCM:MeOH (about 100 mL), 10 g of silica gel was added,and the mixture was concentrated. The resulting mixture was purified bysilica gel chromatography using a gradient of 0-100% DCM/MeOH/Et₂NH(990:9:1) to DCM/MeOH/Et₂NH (970:27:3). The product-containing fractionswere combined and concentrated to give a white solid. The solid wasdissolved in boiling EtOH (150 mL) and sonicated for about 1 h. Thesolvent was removed under reduced pressure and the solid was dried in avacuum oven at about 70° C. for about 72 h. Water (12 mL) and EtOH (3mL) were added, and the resulting slurry was refluxed for 2 h. Theslurry was cooled to ambient temperature, followed by further cooling atabout 0° C. in an ice bath. The solids were filtered while rinsing withice-cooled water (about 3 mL) and dried in a vacuum oven to giveN-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1, 2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.5g, 10.4%) as a white solid with 0.5% EtOH: LC/MS (Table 2, Method a)R_(t)=1.61 min; MS m/z: 361 (M+H)⁺.

Example #15N-((1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide

Step A: Sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate

A round bottom flask was charged with THF (1.5 L) followed by theportion-wise addition of sodium hydride (60% dispersion in mineral oil,70.0 g, 1.75 mol). Additional THF (500 mL) was added and the resultingmixture was cooled to about −10° and ethyl propionylacetate (250 mL, 1.8mol) was added drop-wise over about 1 h in order to keep internaltemperature below about 10° C. The resulting mixture was stirred atambient temperature for about 0.5 h to give a clear yellow solution, andmethyl 4-chloroacetoacetate (100 mL, 0.88 mol) was added drop-wise overabout 5 min. The resulting mixture was heated to about 50° C. for about19 h to give a reddish orange suspension. The reaction mixture was thenconcentrated under reduced pressure and the resulting liquid wastransferred to a beaker and diluted with water (350 mL). The mixture wasstirred and placed in an ice bath for about 2 h. The solid was collectedby vacuum filtration and the filter cake was rinsed with water (150 mL)and dried under vacuum. The solid was suspended in Et₂O (1.5 L),filtered, washed with Et₂O (1.5 L), and dried under vacuum. Theresulting solid was azeotroped with toluene (1 L) to give a solid thatwas re-suspended in Et₂O (1 L) and collected by vacuum filtration. Thefilter cake was washed with Et₂O (500 mL) and dried under vacuum to givesodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(204.2 g, 89%) as beige solid: ¹H NMR (DMSO-d₆) δ 3.94 (q, J=7.1 Hz,2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66 (s, 2H), 1.13 (t, J=7.1Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).

Step B: Ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate

A round-bottom flask was charged with sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(250 g, 0.94 mol) and diglyme (1.1 L) to give a green suspension,followed by AcOH (140 mL, 2.4 mol). To the resulting mixture was addedsodium iodide (490 g, 3.3 mol) portion-wise over about 5-10 min. Uponaddition, the temperature rose from about 16° C. to about 36° C. Thereaction mixture was then heated to reflux for about 3 h, cooled to roomtemperature, and poured over a mixture of ice (2 L) and saturatedaqueous NaHCO₃ (4 L). The resulting material was extracted with Et₂O(4×1.2 L) and the combined organic layers were dried over anhydrousMgSO₄ and filtered. The solvent was removed under reduced pressure togive a brown liquid (250 mL) that was purified by vacuum distillation(80-92° C., 0.3 Torr) to give ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate (95.7 g, 56%) as a yellow syrup:¹H NMR (CDCl₃) δ 6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69 (m, 1H),2.75-2.57 (m, 2H), 2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H), 1.23-1.18 (m,3H).

Step C: Ethyl 2-ethyl-4-oxocyclopentanecarboxylate

A round-bottom flask was charged with 10% palladium on carbon (10 g, 9.4mmol). The flask was cooled to about 0° C. and EtOAc (400 mL) was addedunder a nitrogen atmosphere. The cooling bath was removed and ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate (47.8 g, 263 mmol) was added.Hydrogen gas was bubbled through the mixture for about 5 min and themixture was then stirred under a hydrogen atmosphere for about 48 h. Thehydrogen source was removed, the mixture was bubbled with nitrogen forabout 5 min and was filtered through a pad of Celite®. The filter cakewas rinsed with EtOAc (400 mL). The filtrate was concentrated underreduced pressure to give ethyl 2-ethyl-4-oxocyclopentanecarboxylate(48.0 g, 99%) as a yellow liquid: ¹H NMR (CDCl₃) δ 4.23-4.10 (m, 2H),3.22 (m, 1H), 2.59-2.50 (m, 1H), 2.44-2.28 (m, 3H), 2.26-2.16 (m, 1H),1.58-1.46 (m, 1H), 1.41-1.30 (m, 1H), 1.30-1.23 (m, 3H), 1.02-0.91 (m,3H).

Step D: Ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate

A round-bottom flask was charged with ethyl2-ethyl-4-oxocyclopentanecarboxylate (95.9 g, 521 mmol) and DCE (1.8 L).The solution was cooled to about 0° C. and glacial AcOH (45 mL, 780mmol) and dibenzylamine (120 mL, 625 mmol) were added drop-wise,resulting in formation of a thick suspension. The reaction mixture waswarmed to about 10° C. by removing the cooling bath and additional DCE(500 mL) was added. Sodium triacetoxyborohydride (166 g, 781 mmol) wasadded portion-wise and the reaction mixture was stirred at roomtemperature for about 20 h. The reaction mixture was slowly poured intostirred saturated aqueous NaHCO₃ (1.5 L), followed by the portion-wiseaddition of solid NaHCO₃ (175 g, 2083 mmol). The mixture was stirred forabout 2 h and the organic layer was separated, dried over anhydrousNa₂SO₄, and concentrated to dryness under reduced pressure. The crudeyellow oil was purified on silica gel column chromatography eluting witha gradient of 0-20% EtOAc/heptane. The solvent was removed under reducedpressure to yield ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate(136.6 g, 72%) as a white solid: LC MS (Table 2, Method a) R_(t)=3.26min; MS m/z: 366 (M+H)⁺.

Step E: Ethyl 4-amino-2-ethylcyclopentanecarboxylate

To a vessel containing a slurry of 20% wet Pd(OH)₂—C (12.9 g, 92.0 mmol)in EtOH (1.0 L) was added ethyl4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (129 g, 352 mmol). Thereaction was shaken for about 90 min at about 50° C. at about 30 psi ofH₂. The resulting mixture was filtered through a nylon membrane and thefiltrate was concentrated under reduced pressure to give ethyl4-amino-2-ethylcyclopentanecarboxylate (64.5 g, 99%) as a yellow syrup:¹H NMR (CDCl₃) δ 4.03-3.88 (m, 2H), 3.17 (m, 1H), 2.68 (m, 1H),2.09-2.02 (m, 2H), 2.02-1.94 (m, 2H), 1.84 (m, 1H), 1.58-1.48 (m, 1H),1.32-1.18 (m, 1H), 1.09 (m, 3H), 1.03 (m, 2H), 0.78-0.69 (m, 3H).

Step F: (1S,2R,4S)-Ethyl4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylate

A solution of ethyl 4-amino-2-ethylcyclopentanecarboxylate (20.5 g, 111mmol) in DMF (340 mL) was cooled to about 0° C. in an ice bath. TEA(38.6 mL, 277 mmol) was added and stirring was continued at about 0° C.for about 15 min and then cyclopropanesulfonyl chloride (15.6 g, 111mmol, Matrix) was added drop-wise. The resulting solution was stirred atabout 0° C. for about 2 h. The ice bath was removed and the reactionmixture continued stirring at ambient temperature for about 3 h. Thereaction was concentrated under reduced pressure and EtOAc (200 mL) andwater (60 mL) were added. The layers were separated and the organiclayer was washed with saturated aqueous NaHCO₃ (60 mL) and brine (60mL), dried over anhydrous MgSO₄, filtered, and concentrated underreduced pressure to give a reddish brown oil. The crude material waspurified by silica gel chromatography eluting with a step-wise gradientof 10% EtOAc in heptane then 15% EtOAc in heptane followed by 20% EtOAcin heptane to give a yellow oil (27.3 g) that was purified by chiralpreparative HPLC (Table 3, Method 9, R_(t)=9.5 min, or =negative) togive (1S,2R,4S)-ethyl4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylate (11.1 g,35%): LC/MS (Table 2, Method a) R_(t)=2.25 min; MS m/z: 290 (M+H)⁺.

Step G:(1S,2R,4S)-4-(Cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylicacid

To a flask containing (1S,2R,4S)-ethyl4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylate (11.1 g, 38.4mmol) was added 1 N aqueous NaOH (210 mL, 210 mmol). After stirring atambient temperature for about 8 h, the reaction was acidified to aboutpH 1 with 6 N aqueous HCl and extracted with DCM (3×150 mL). Thecombined organic layers were washed with brine, dried over anhydrousMgSO₄, filtered, and concentrated under reduced pressure to give crude(1S,2R,4S)-4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylicacid containing about 25 mol % DCM (10.7 g, 99%): LC/MS (Table 2, Methoda) R_(t)=1.71 min; MS m/z: 260 (M−H)⁻.

Step H: 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (78.0 g, 394 mmol, ArkPharm) in anhydrous DMF (272 mL) was added drop-wise over about 60 minto a stirred suspension of NaH (60% dispersion in mineral oil, 12.8 g,532 mmol) in anhydrous DMF (543 mL) at about 0-5° C. The brown reactionsolution was stirred for about 30 min at about 0-5° C. then a solutionof p-toluenesulfonyl chloride (94.0 g, 492 mmol) in anhydrous DMF (272mL) was added drop-wise over about 60 min at about 0-5° C. The reactionmixture was stirred at about 0-5° C. for about 1 h then allowed to warmto ambient temperature and stirred for about 18 h. The reaction mixturewas poured slowly into ice water (6 L), followed by the addition ofaqueous NaOH (2.5 M, 50.0 mL, 125 mmol). The precipitate was collectedby filtration and stirred with cold water (3×200 mL). The solid wascollected by filtration and dried to constant weight in a vacuum oven atabout 55° C. to yield 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (134.6g, 97%) as a pale beige solid: LC/MS (Table 2, Method d) R_(t)=1.58 min;MS m/z: 352/354 (M+H)⁺.

Step I: tert-Butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate

To a flask was added Pd₂(dba)₃ (3.90 g, 4.26 mmol),di-tert-butyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (3.62 g,8.52 mmol), and anhydrous 1,4-dioxane (453 mL). The catalyst-ligandmixture was degassed via vacuum/nitrogen purge (3 times) and heated atabout 80° C. for about 10 min. Then2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (30.0 g, 85 mmol), tert-butylhydrazinecarboxylate (16.9 g, 128 mmol), and NaOt-Bu (12.28 g, 128 mmol)were added. After an additional vacuum/nitrogen purge, the reaction washeated at about 80° C. After about 50 min, the reaction mixture wascooled to ambient temperature and filtered through a pad of silica gel(6 cm in height×6 cm in diameter), topped with Celite® (1 cm in height×6cm in diameter), while washing with EtOAc (3×150 mL). Water (300 mL) wasadded to the filtrate and the organic layer was separated. The aqueouslayer was extracted with additional EtOAc (3×200 mL). The combinedorganic extracts were washed with saturated aqueous NH₄Cl, saturatedaqueous NaHCO₃, and brine (400 mL each), dried over anhydrous MgSO₄,filtered, and concentrated under reduced pressure to give a dark brownoil (45 g). The brown oil was dissolved in DCM (250 mL), silica gel (200g) was added, and the mixture was concentrated under reduced pressure.The resulting silica mixture was purified using silica gelchromatography eluting with a gradient of 25-65% EtOAc in heptane togive a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [majorregioisomer] and tert-butyl1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [minorregioisomer] (18.8 g, 50%): LC/MS (Table 2, Method d) R_(t)=1.47 min; MSm/z: 404 (M+H)⁺.

Step J: 2-Hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(18.8 g, 46.6 mmol) in 1,4-dioxane (239 mL) was added HCl (4 M in1,4-dioxane, 86 mL, 345 mmol). The reaction was heated at about 60° C.for about 1 h and then cooled to about 15-20° C. The solid was collectedby vacuum filtration, washed with cold 1,4-dioxane (2×20 mL), and thenstirred with a solution of saturated NaHCO₃ and water (1:1, 150 mL).After about 1 h, the effervescence had subsided and the solid wascollected by vacuum filtration, washed with ice cold water (3×20 mL),and dried in a vacuum oven to a constant weight to afford2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a light yellowishbrown solid (8.01 g, 50%): LC/MS (Table 2, Method d) R_(t)=1.28 min; MSm/z: 304 (M+H)⁺.

Step K:N-((1S,3R,4S)-3-Ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide

To a mixture of(1S,2R,4S)-4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylicacid (8.43 g, 30.1 mmol, Step G) in DCM (160 mL) was added2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (9.20 g, 28.8 mmol, StepJ), HATU (11.5 g, 30.3 mmol) and TEA (16.0 mL, 115 mmol). After stirringat ambient temperature for about 1 h, the reaction was diluted withwater (150 mL). The layers were separated and the aqueous layer wasextracted with DCM (2×150 mL). The combined organic layers were washedwith brine, dried over anhydrous MgSO₄, filtered, and concentrated underreduced pressure. The crude material was dissolved in DCM and purifiedby silica gel chromatography eluting with a gradient of 60-100% EtOAc inheptane. The product-containing fractions were combined, concentratedunder reduced pressure, and dried on a vacuum pump to giveN-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)cyclopropanesulfonamide(14.1 g) as a tan foam containing about 50 mol % tetramethylurea andabout 35 mol % EtOAc. To a solution of impureN-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)-cyclopropanesulfonamide(14.0 g, 22.9 mmol) in 1,4-dioxane (125 mL) was added TEA (13 mL, 93mmol) and thionyl chloride (2.5 mL, 34.3 mmol). The reaction was heatedat about 80° C. for about 2.5 h. Then the reaction was cooled to ambienttemperature and water and EtOAc (150 mL each) were added. The layerswere separated and the aqueous layer was extracted with additional EtOAc(2×100 mL). The combined organic layers were washed with brine (100 mL),dried over anhydrous Na₂SO₄, filtered, concentrated under reducedpressure, and dried under vacuum. The crude material was purified bysilica gel chromatography eluting with a gradient of 60-100% EtOAc inheptane while monitoring at 330 nm. The product-containing fractionswere combined, and concentrated under reduced pressure to give a lightbrown solid. The solid was sonicated with EtOAc (60 mL) for about 10min, left at ambient temperature for about 5 min, collected by vacuumfiltration, while washing with additional EtOAc (20 mL), and dried in avacuum oven at about 60° C. to giveN-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamidewith about 40 mol % EtOAc (8.08 g, 50% over 2 steps): LC/MS (Table 2,Method a) R_(t)=2.30 min; MS m/z: 529 (M+H)⁺.

Step L:N-((1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide

A mixture ofN-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide(8.00 g, 13.8 mmol), 1,4-dioxane (80 mL) and 1 N aqueous NaOH (30.0 mL,30.0 mmol) was heated at about 60° C. for about 2 h. Then the reactionwas diluted with water (100 mL) and extracted with EtOAc (3×100 mL). Thecombined organic layers were washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Thecrude mixture was purified by silica gel chromatography eluting with agradient of 0-100% DCM/MeOH/Et₂NH (970:27:3) in DCM followed byDCM/MeOH/Et₂NH (950:45:5). The product-containing fractions werecombined, concentrated under reduced pressure, and dried in a vacuumoven at about 70° C. for about 12 h to give a solid. The solid wastriturated with Et₂O, filtered while washing with additional Et₂O, anddissolved in hot MeOH. The solution was concentrated under reducedpressure to give a solid. The solid was dissolved in hot MeOH (200 mL),sonicated while cooling until a suspension formed, concentrated underreduced pressure, and dried in a vacuum oven at about 50° C. to give anoff-white solid. To the solid was added EtOAc (30 mL) to give asuspension which was heated briefly with a heat gun and then sonicatedfor about 15 min. After sitting at ambient temperature for about 15 min,the resulting white solid was collected by vacuum filtration, washingwith additional EtOAc (15 mL), and dried in a vacuum oven at about 50°C. The solid was dissolved in hot EtOH (˜200 mL), filtered to removeminor insolubles (<10 mg), sonicated for about 10 min, while cooling, togive a white suspension, which was concentrated under reduced pressure.The resulting white solid was dried in a vacuum oven at about 60° C. togive N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1, 2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (3.43g, 67%): LC/MS (Table 2, Method a) R_(t)=1.67 min; MS m/z: 375 (M+H)⁺.

Example #16(R)-1-(3-(3H-Imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carbonyl)cyclopropanecarbonitrile

Step A: tert-Butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate

To a flask was added Pd₂(dba)₃ (1.3 g, 1.4 mmol),di-tert-butyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (1.21 g,2.84 mmol), and 1,4-dioxane (75 mL). The catalyst-ligand mixture wasdegassed via vacuum/nitrogen purge (3 times) and heated at about 80° C.for about 10 min. 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (5.0 g, 14mmol, Preparation #7), tert-butyl carbamate (2.5 g, 21 mmol), andNaOt-Bu (2.05 g, 21.3 mmol) were added. After an additionalvacuum/nitrogen purge, the reaction was heated at about 80° C. for about16 h. The reaction was cooled to ambient temperature and diluted withEtOAc (70 mL). The reaction mixture was filtered and the filtrate waswashed with water (3×20 mL). The organic layer was dried over anhydrousMgSO₄, filtered, and solvent removed under reduced pressure to give areddish-brown solid. The crude material was purified by silica gelchromatography eluting with a gradient of 10-50% EtOAc in heptane toyield tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate as ayellow amorphous solid (1.0 g, 18%): LC/MS (Table 2, Method a)R_(t)=2.63 min; MS m/z: 389 (M+H)⁺.

Step B: (R)-(9H-Fluoren-9-yl)methyl3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)piperidine-1-carboxylate

NaH (60% dispersion in mineral oil, 0.041 g, 1.0 mmol) was added toanhydrous DMF (5 mL). The suspension was cooled to about 0° C. and asolution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate(0.40 g, 1.0 mmol) in anhydrous DMF (5 mL) was added drop-wise. Thereaction mixture was allowed to warm to ambient temperature and(R)-(9H-fluoren-9-yl)methyl 3-(2-bromoacetyl)piperidine-1-carboxylate(0.441 g, 1.03 mmol, Preparation #LL.1) was added. The reaction mixturewas stirred for about 30 min before it was partitioned between EtOAc (30mL) and brine (2×100 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (12 g column) eluting with agradient of 10-50% EtOAc in heptane to give(R)-(9H-fluoren-9-yl)methyl-3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)piperidine-1-carboxylateas a clear oil (0.21 g, 26%): LC/MS (Table 2, Method a) R_(t)=3.16 min;MS m/z: 736 (M+H)⁺.

Step C: (R)-(9H-Fluoren-9-yl)methyl3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate

A mixture of (R)-(9H-fluoren-9-yl)methyl3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)piperidine-1-carboxylate(0.20 g, 0.27 mmol), TFA (1.0 mL, 13 mmol) and TFAA (1.0 mL, 7.1 mmol)was stirred at about 25° C. for about 16 h. The reaction mixture waspartitioned between EtOAc (50 mL) and aqueous saturated NaHCO₃ (2×50mL). The organic layer was separated, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure to give(R)-(9H-fluoren-9-yl)methyl3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylateas a clear oil (0.17 g, 99%): LC/MS (Table 2, Method a) R_(t)=2.68 min;MS m/z: 618 (M+H)⁺.

Step D:(R)-1-(3-(3H-Imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carbonyl)cyclopropanecarbonitrile

To a solution of (R)-(9H-fluoren-9-yl)methyl3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate(0.20 g, 0.32 mmol) in 1,4-dioxane (3 mL) was added aqueous NaOH (2 N,0.97 mL, 1.9 mmol). The reaction mixture was heated at about 100° C. forabout 3 h before it was allowed to cool to ambient temperature. Thereaction was neutralized with 4N HCl in 1,4-dioxane (0.5 mL) and wasconcentrated under reduced pressure. To the residue was added MeCN (25mL) before it was concentrated under reduced pressure. This procedurewas repeated before the addition of 1-cyanocyclopropanecarboxylic acid(0.072 g, 0.65 mmol), HATU (0.111 g, 0.291 mmol) and DMF (2 mL) followedby DIEA (0.170 mL, 0.971 mmol). After stirring at room temperature forabout 3 h, the reaction was partitioned between EtOAc (2×50 mL) andaqueous NaHCO₃ (50 mL). The combined organic layers were dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Thecrude reaction was purified by RP-HPLC (Table 2, Method j). The combinedproduct-containing fractions were concentrated under reduced pressure toremove MeCN and then lyophilized to give(R)-1-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carbonyl)cyclopropanecarbonitrileas a white solid (0.010 g, 9%): LC/MS (Table 2, Method a) R_(t)=1.67min; MS m/z: 335 (M+H)⁺.

Example #175-((1S,3R)-3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile

Step A: 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (78.0 g, 394 mmol, ArkPharm) in anhydrous DMF (272 mL) was added drop-wise over about 60 minto a stirred suspension of NaH (12.8 g, 532 mmol) in anhydrous DMF (543mL) at about 0-5° C. The brown reaction solution was stirred for about30 min at about 0-5° C. then a solution of p-toluenesulfonyl chloride(94.0 g, 492 mmol) in anhydrous DMF (272 mL) was added drop-wise overabout 60 min at about 0-5° C. The reaction mixture was stirred at about0-5° C. for about 1 h then allowed to warm to ambient temperature andstirred for about 18 h at ambient temperature. The reaction mixture waspoured slowly into ice water (6 L), followed by the addition of aqueous2.5 N NaOH (50.0 mL, 125 mmol). The precipitate was collected byfiltration and stirred with cold water (3×200 mL). The solid wascollected by filtration and dried in air over about 3 days and finallydried to constant weight in a vacuum oven at about 55° C. to yield2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (134.6 g, 97%) as a pale beigesolid: LC/MS (Table 2, Method d) R_(t)=1.58 min; MS m/z: 352/354 (M+H)⁺.

Step B: tert-Butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate

To a flask was added Pd₂(dba)₃ (3.90 g, 4.26 mmol),di-tert-butyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (3.62 g,8.52 mmol), and anhydrous 1,4-dioxane (453 mL). The catalyst-ligandmixture was degassed via vacuum/nitrogen purge (3 times) and heated atabout 80° C. for about 10 min. 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine(30.0 g, 85 mmol Preparation #7), tert-butyl hydrazinecarboxylate (16.9g, 128 mmol), and NaOt-Bu (12.28 g, 128 mmol) were subsequently added.After an additional vacuum/nitrogen purge, the reaction was heated atabout 80° C. After about 50 min, the reaction mixture was cooled toambient temperature and filtered through through a pad of silica gel (6cm in height×6 cm in diameter), topped with Celite® (1 cm in height×6 cmin diameter), while washing with EtOAc (3×150 mL). Water (300 mL) wasadded to the filtrate and the organic layer was separated. The aqueouslayer was extracted with additional EtOAc (3×200 mL). The combinedorganic extracts were washed with saturated aqueous NH₄Cl, saturatedaqueous NaHCO₃, and brine (400 mL each), dried over anhydrous MgSO₄,filtered, and concentrated under reduced pressure to give a dark brownoil (45 g). The brown oil was dissolved in DCM (250 mL), silica gel (200g) was added, and the mixture was concentrated under reduced pressure.The resulting silica mixture was purified using silica gelchromatography eluting with a gradient of 25-65% EtOAc in heptane togive a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [majorregioisomer] and tert-butyl1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [minorregioisomer] (18.8 g, 50%): LC/MS (Table 2, Method d) R_(t)=1.47 min; MSm/z: 404 (M+H)⁺.

Step C: 2-Hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(18.8 g, 46.6 mmol) in 1,4-dioxane (239 mL) was added HCl (4 M in1,4-dioxane, 86 mL, 345 mmol). The reaction was heated at about 60° C.for about 1 h and then cooled to about 15-20° C. The solid was collectedby vacuum filtration, washed with cold 1,4-dioxane (2×20 mL), and thenstirred with a solution of saturated aqueous NaHCO₃ and water (1:1, 150mL). After about 1 h, the effervescence had subsided and the solid wascollected by vacuum filtration, washed with ice cold water (3×20 mL),and dried in a vacuum oven to afford2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a light yellowishbrown solid (8.01 g, 50%): LC/MS (Table 2, Method d) R_(t)=1.28 min; MSm/z: 304 (M+H)⁻.

Step D: tert-Butyl(1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate

To mixture of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.50 g,8.24 mmol) and(1R,3S)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (2.08 g,9.07 mmol, Peptech) in DCM (30 mL) was added EDC.HCl (1.90 g, 9.89mmol). After stirring for about 4.5 h at ambient temperature, water (30mL) was added and the layers were separated. The aqueous layer was thenextracted with EtOAc (15 mL). The combined organic layers were washedwith brine, dried over anhydrous MgSO₄, filtered, and concentrated underreduced pressure. The crude material was dissolved in DCM (15 mL) andpurified by silica gel chromatography eluting with a gradient of 40-100%EtOAc in heptane to give tert-butyl(1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate(4.20 g, 97%): LC/MS (Table 2, Method a) R_(t)=2.27 min; MS m/z: 515(M+H)⁺.

Step E:tert-Butyl-(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate

To a solution of tert-butyl(1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate(9.30 g, 18.1 mmol) in 1,4-dioxane (100 mL) was added TEA (10.0 mL, 72.3mmol) and SOCl₂ (2.11 mL, 28.9 mmol). The mixture was heated at about80° C. for about 1.5 h. The reaction mixture was cooled to ambienttemperature, EtOAc and water were added, and the layers were separated.The aqueous solution was extracted with EtOAc (2×100 mL) and thecombined organic layers were washed with saturated aqueous NaHCO₃ andbrine (100 mL each). The organic extracts were dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. The crudematerial was purified by silica gel chromatography eluting with agradient of 25-100% EtOAc in DCM to givetert-butyl-(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1, 2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate (7.65 g, 85%): LC/MS(Table 2, Method a) R_(t)=2.37 min; MS m/z: 497 (M+H)⁺.

Step F:(1S,3R)-3-(6-Tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanaminehydrochloride

To a solution of tert-butyl(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate(8.22 g, 16.6 mmol) in 1,4-dioxane (32 mL) was added HCl (4 N in1,4-dioxane, 16.6 mL, 66.2 mmol), and the reaction mixture was heated atabout 60° C. for about 1.5 h then stirred at ambient temperatureovernight. The reaction mixture was filtered, while rinsing with Et₂O(100 mL). The filter cake was dried under vacuum to give a light brownsolid that was further dried in a vacuum oven at about 50° C. to give(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanaminehydrochloride (7.61 g, 93%) as a beige solid: LC/MS (Table 2, Method d)R_(t)=1.09 min; MS m/z: 397 (M+H)⁺.

Step G:5-((1S,3R)-3-(6-Tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile

To a microwave vessel was added(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanaminehydrochloride (0.500 g, 1.06 mmol), n-propanol (10 mL),5-chloropyrazine-2-carbonitrile (0.223 g, 1.60 mmol) and DIEA (0.837 mL,4.79 mmol). The resulting mixture was heated in a microwave at about150° C. for about 30 min. DCM (100 mL) was added and a solution wasformed. The organic solution was washed with water and brine (50 mLeach), dried over anhydrous MgSO₄, filtered, and concentrated underreduced pressure to give a brown solid. The residue was taken up in DCM(30 mL) and adsorbed onto silica gel (5 g). The material was purified bysilica gel chromatography (80 g cartridge) eluting with neat EtOAc togive5-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile(0.43 g, 80%) as a light yellow solid: LC/MS (Table 2, Method d)R_(t)=1.40 min; MS m/z: 500 (M+H)⁺.

Step H:5-((1S,3R)-3-(6H-Pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile

A mixture of5-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile(0.426 g, 0.853 mmol) and aqueous NaOH (1 N, 1.71 mL, 1.71 mmol) in1,4-dioxane (4.4 mL) was heated at about 60° C. for about 80 min. Themixture was cooled to ambient temperature and diluted with water (40mL). A solid precipitated and was collected by vacuum filtration andwashed with water to give an off-white solid. The material was dissolvedin hot EtOH and allowed to cool to ambient temperature. The precipitatewas collected by filtration and dried under vacuum to give an off-whitesolid that was dried in a vacuum oven at about 70° C. to give anoff-white solid (0.199 g). The material was taken up in EtOAc (10 mL)and heated at about 70° C. for about 1.5 h. The solid was collected byvacuum filtration, while rinsing with EtOAc. This material was driedunder vacuum to give5-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile(0.19 g, 64%) as an off-white solid: LC/MS (Table 2, Method a)R_(t)=1.55 min; MS m/z: 346 (M+H)⁺.

Example #185-((1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrileand5-((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile

Step A: Sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate

A round bottom flask was charged with THF (1.5 L) followed by theportion-wise addition of sodium hydride (60% dispersion in mineral oil,70.0 g, 1.75 mol). Additional THF (500 mL) was added. The resultingmixture was cooled to about −10° and ethyl propionylacetate (250 mL, 1.8mol) was added drop-wise over about 1 h in order to keep internaltemperature below about 10° C. The resulting mixture was stirred atambient temperature for about 0.5 h to give a clear yellow solution, andmethyl 4-chloroacetoacetate (100 mL, 0.88 mol) was added drop-wise overabout 5 min. The resulting mixture was heated to about 50° C. for about19 h to give a reddish orange suspension. The reaction mixture was thenconcentrated under reduced pressure and the resulting liquid was dilutedwith water (350 mL). The mixture was stirred and placed in an ice bathfor about 2 h. The solid was collected by vacuum filtration and thefilter cake was rinsed with water (150 mL) and dried under vacuum. Thesolid was suspended in Et₂O (1.5 L), filtered, washed with Et₂O (1.5 L),and dried under vacuum. The resulting solid was azeotroped with toluene(1 L) to give a solid that was re-suspended in Et₂O (1 L) and collectedby vacuum filtration. The filter cake was washed with Et₂O (500 mL) anddried under vacuum to give sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(204.2 g, 89%) as beige solid: ¹H NMR (DMSO-d₆) δ 3.94 (q, J=7.1 Hz,2H), 3.46 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.66 (s, 2H), 1.13 (t, J=7.1Hz, 3H), 0.99 (t, J=7.3 Hz, 3H).

Step B: Ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate

A round-bottom flask was charged with sodium4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-dienolate(250 g, 0.94 mol) and diglyme (1.1 L) to give a green suspension,followed by AcOH (140 mL, 2.4 mol). To the resulting mixture was addedsodium iodide (490 g, 3.3 mol) portion-wise over about 5-10 min. Uponaddition, the temperature rose from about 16° C. to about 36° C. Thereaction mixture was then heated to reflux for about 3 h, cooled to roomtemperature, and poured over a mixture of ice (2 L) and saturatedaqueous NaHCO₃ (4 L). The resulting material was extracted with Et₂O(4×1.2 L) and the combined organic layers were dried over anhydrousMgSO₄ and filtered. The solvent was removed under reduced pressure togive a brown liquid (250 mL) that was purified by vacuum distillation(80-92° C., 0.3 Torr) to give ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate (95.7 g, 56%) as a yellow syrup:¹H NMR (CDCl₃) δ 6.04 (m, 1H), 4.26-4.15 (m, 2H), 3.76-3.69 (m, 1H),2.75-2.57 (m, 2H), 2.56-2.44 (m, 2H), 1.32-1.26 (m, 3H), 1.23-1.18 (m,3H).

Step C: Ethyl 2-ethyl-4-oxocyclopentanecarboxylate

A round-bottom flask was charged with 10% palladium on carbon (10 g, 9.4mmol). The flask was cooled to about 0° C. and EtOAc (400 mL) was addedunder a nitrogen atmosphere. The cooling bath was removed and ethyl2-ethyl-4-oxocyclopent-2-enecarboxylate (47.8 g, 263 mmol) was added.Hydrogen gas was bubbled through the mixture for about 5 min and themixture was then stirred under a hydrogen atmosphere for about 48 h atambient temperature. The hydrogen source was removed, the mixture wasbubbled with nitrogen for about 5 min and was filtered through a pad ofCelite®. The filter cake was rinsed with EtOAc (400 mL). The filtratewas concentrated under reduced pressure to give ethyl2-ethyl-4-oxocyclopentanecarboxylate (about 9:1 mixture cis:trans) (48.0g, 99%) as a yellow liquid: ¹H NMR (CDCl₃) δ 4.23-4.10 (m, 2H), 3.22 (m,1H), 2.59-2.50 (m, 1H), 2.44-2.28 (m, 3H), 2.26-2.16 (m, 1H), 1.58-1.46(m, 1H), 1.41-1.30 (m, 1H), 1.30-1.23 (m, 3H), 1.02-0.91 (m, 3H).

Step D: Ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate

A round-bottom flask was charged with ethyl2-ethyl-4-oxocyclopentanecarboxylate (95.9 g, 521 mmol) and DCE (1.8 L).The solution was cooled to about 0° C. and AcOH (45 mL, 780 mmol) anddibenzylamine (120 mL, 625 mmol) were added drop-wise, resulting in theformation of a thick suspension. The reaction mixture was warmed toabout 10° C. by removing the cooling bath and additional DCE (500 mL)was added. Sodium triacetoxyborohydride (166 g, 781 mmol) was addedportion-wise and the reaction mixture was stirred at room temperaturefor about 20 h. The reaction mixture was slowly poured into saturatedaqueous NaHCO₃ (1.5 L) with stirring followed by the portion-wiseaddition of solid NaHCO₃ (175 g, 2083 mmol). The mixture was stirred forabout 2 h and the organic layer was separated, dried over anhydrousNa₂SO₄, and concentrated to dryness under reduced pressure. The crudeyellow oil was purified by flash column chromatography usingEtOAc/heptane as eluant (0-20% EtOAc) to yield ethyl4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (136.6 g, 72%) as awhite solid: LC/MS (Table 2, Method a) R_(t)=3.26 min; MS m/z: 366(M+H)⁺.

Step E: Ethyl 4-amino-2-ethylcyclopentanecarboxylate

To a vessel containing a slurry of 20% wet Pd(OH)₂—C (12.9 g, 92.0 mmol)in EtOH (1.0 L) was added ethyl4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (129 g, 352 mmol). Thereaction was shaken for about 90 min at about 50° C. under about 30 psiof H₂. The resulting mixture was filtered through a pad of Celite® andthe filtrate was concentrated under reduced pressure to give ethyl4-amino-2-ethylcyclopentanecarboxylate (64.5 g, 99%) as a yellow syrup:¹H NMR (CDCl₃) δ 4.03-3.88 (m, 2H), 3.17 (m, 1H), 2.68 (m, 1H),2.09-2.02 (m, 2H), 2.02-1.94 (m, 2H), 1.84 (m, 1H), 1.58-1.48 (m, 1H),1.32-1.18 (m, 1H), 1.09 (m, 3H), 1.03 (m, 2H), 0.78-0.69 (m, 3H).

Step F: (Ethyl4-(tert-butoxycarbonylamino)-2-ethylcyclopentanecarboxylate

A 250 mL round-bottomed flask was charged with ethyl4-amino-2-ethylcyclopentanecarboxylate (1.96 g, 10.6 mmol) and DCM (100mL) to give a colorless solution. The solution was cooled to about 10°C. and TEA (3.70 mL, 26.5 mmol) and di-tert-butyl dicarbonate (2.77 g,12.7 mmol) were added. The resulting solution was stirred at about 0° C.for about 1 h, then the mixture was slowly warmed to room temperatureand stirred for about 16 h. Brine (10 mL) was added and the layers werepartitioned. The organic layer was dried over anhydrous MgSO₄, filtered,and the solvent was removed under reduced pressure to give (ethyl4-(tert-b toxycarbonylamino)-2-ethylcyclopentanecarboxylate (3.3 g, 90%purity by NMR, 98%) as a cloudy oil: ¹H NMR (CDCl₃) δ 5.22-5.19 (m, 1H), 4.18-4.07 (m, 3 H), 2.86-2.81 (m, 1 H), 2.33-2.26 (m, 1 H),2.24-2.16 (m, 1 H), 2.03-1.94 (m, 1 H), 1.76-1.71 (m, 1 H), 1.48-1.41(m, 1 H), 1.43 (s, 9 H), 1.27 (t, 3H), 1.27-1.21 (m, 2 H), 0.92 (t, 3H).

Step G: 4-(tert-Butoxycarbonylamino)-2-ethylcyclopentanecarboxylic acid

A 250 mL round-bottomed flask was charged with ethyl4-(tert-butoxycarbonylamino)-2-ethylcyclopentanecarboxylate (3.00 g,10.5 mmol) in THF (96 mL) to give a colorless solution. An aqueoussolution of NaOH (1 N, 16.0 mL, 16.0 mmol) was added and the reactionmixture was stirred for about 24 h at ambient temperature. Additionalaqueous NaOH (1 N, 5.00 mL, 5.00 mmol) was added and stirring wascontinued for about 48 h at room temperature. The reaction mixture washeated to about 50° C. for about 24 h. The solvent was removed underreduced pressure. AcOH was added until pH 5 was reached. EtOAc (50 mL)was added and the layers were partitioned. The aqueous layer was furtherextracted with EtOAc (2×30 mL). The combined organic extracts were driedover anhydrous MgSO₄, filtered, and concentrated under reduced pressureto give a yellow oil. The oil was further dried under high vacuum,resulting in formation of a solid that was dissolved in DCM andconcentrated to dryness, re-suspended in DCM and re-concentrated todryness. The residue was then suspended in Et₂O and concentrated todryness and further dried under vacuum for about 3 h to give4-(tert-butoxycarbonylamino)-2-ethylcyclopentanecarboxylic acid (2.36 g,87%): LC/MS (Table 2, Method a) R_(t)=2.09 min; MS m/z: 256 (M−H)⁻.

Step H: 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (78.0 g, 394 mmol, ArkPharm) in anhydrous DMF (272 mL) was added drop-wise over about 60 minto a stirred suspension of NaH (12.8 g, 532 mmol) in anhydrous DMF (543mL) at about 0-5° C. The brown reaction solution was stirred for about30 min at about 0-5° C. then a solution of p-toluenesulfonyl chloride(94.0 g, 492 mmol) in anhydrous DMF (272 mL) was added drop-wise overabout 60 min at about 0-5° C. The reaction mixture was stirred at about0-5° C. for about 1 h then allowed to warm to ambient temperature andstirred for about 18 h at ambient temperature. The reaction mixture waspoured slowly into ice water (6 L), followed by the addition of aqueous2.5 N NaOH (50.0 mL, 125 mmol). The precipitate was collected byfiltration and stirred with cold water (3×200 mL). The solid wascollected by filtration and dried to constant weight in a vacuum oven atabout 55° C. to yield 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (134.6g, 97%) as a pale beige solid: LC/MS (Table 2, Method d) R_(t)=1.58 min;MS m/z: 352/354 (M+H)⁺.

Step I: tert-Butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate

To a flask was added Pd₂(dba)₃ (3.90 g, 4.26 mmol),di-tert-butyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (3.62 g,8.52 mmol), and anhydrous 1,4-dioxane (453 mL). The catalyst-ligandmixture was degassed via vacuum/nitrogen purge (3 times) and heated atabout 80° C. for about 10 min. 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine(30.0 g, 85 mmol), tert-butyl hydrazinecarboxylate (16.9 g, 128 mmol),and NaOt-Bu (12.28 g, 128 mmol) were subsequently added. After anadditional vacuum/nitrogen purge, the reaction was heated at about 80°C. After about 50 min, the reaction mixture was cooled to ambienttemperature and filtered through through a pad of silica gel (6 cm inheight×6 cm in diameter), topped with Celite® (1 cm in height×6 cm indiameter), while washing with EtOAc (3×150 mL). Water (300 mL) was addedto the filtrate and the organic layer was separated. The aqueous layerwas extracted with additional EtOAc (3×200 mL). The combined organicextracts were washed with saturated aqueous NH₄Cl, saturated aqueousNaHCO₃, and brine (400 mL each), dried over anhydrous MgSO₄, filtered,and concentrated under reduced pressure to give a dark brown oil (45 g).The brown oil was dissolved in DCM (250 mL), silica gel (200 g) wasadded, and the mixture was concentrated under reduced pressure. Theresulting silica mixture was purified using silica gel chromatographyeluting with a gradient of 25-65% EtOAc in heptane to give a mixture oftert-butyl 2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate[major regioisomer] and tert-butyl1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate [minorregioisomer] (18.8 g, 50%): LC/MS (Table 2, Method d) R_(t)=1.47 min; MSm/z: 404 (M+H)⁺.

Step J: 2-Hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

To a mixture of tert-butyl2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate andtert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(18.8 g, 46.6 mmol) in 1,4-dioxane (239 mL) was added HCl (4 M in1,4-dioxane, 86 mL, 345 mmol). The reaction was heated at about 60° C.for about 1 h and then cooled to about 15-20° C. The solid was collectedby vacuum filtration, washed with cold 1,4-dioxane (2×20 mL), and thenstirred with a solution of saturated NaHCO₃ and water (1:1, 150 mL).After about 1 h, the effervescence had subsided and the solid wascollected by vacuum filtration, washed with ice cold water (3×20 mL),and dried in a vacuum oven to a constant weight to afford2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a light yellowishbrown solid (8.01 g, 50%): LC/MS (Table 2, Method d) R_(t)=1.28 min; MSm/z: 304 (M+H)⁺.

Step K:tert-Butyl-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate

A round-bottomed flask was charged with2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.0 g, 6.6 mmol, Step J)and DCM (40 mL) to give a brown suspension.4-(tert-Butoxycarbonylamino)-2-ethylcyclopentanecarboxylic acid (2.0 g,7.8 mmol, Step G), HATU (2.51 g, 6.59 mmol), and TEA (4.59 mL, 33.0mmol) were added to the suspension and the resulting mixture was stirredat ambient temperature for about 24 h with dissolution occurring afterabout 2 h. Water (20 mL) was added and the layers were partitioned. Theorganic layer was washed with additional water (2×15 mL), brine (2×25mL), dried over anhydrous MgSO₄, filtered, and solvent was removed underreduced pressure to give a brown residue. The crude material waspurified by silica gel chromatography eluting with a gradient of 0-10%MeOH/DCM. The recovered impure material was re-purified by silica gelchromatography eluting with a gradient of 0-10% MeOH/DCM. Theproduct-containing fractions from the two columns were combined andconcentrated to givetert-butyl-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate(2.45, 69%) as a brown solid: LC/MS (Table 2, Method d) R_(t)=1.47 min;MS m/z: 543 (M+H)⁺.

Step L:tert-Butyl-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate

A round-bottomed flask was charged withtert-butyl-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate(2.45 g, 4.55 mmol) and 1,4-dioxane (24 mL) to give a brown solution.TEA (2.54 mL, 18.2 mmol) was added followed by the addition of SOCl₂(0.50 mL, 6.8 mmol). The reaction mixture was heated at about 80° C. forabout 5 h. The mixture was cooled to ambient temperature and EtOAc (100mL) and water (30 mL) were added. The layers were partitioned and theorganic layer was washed with water (2×30 mL) and brine (2×30 mL), driedover anhydrous MgSO₄, filtered, and the solvent was removed underreduced pressure to give a brown residue. The crude material waspurified by silica gel chromatography eluting with a gradient of 0-10%MeOH/DCM. The product-containing fractions were combined andconcentrated to give tert-butyl(1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate(1.7 g, 71%): LC/MS (Table 2, Method a) R_(t)=2.50 min; MS m/z: 525(M+H)⁺.

Step M:3-Ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine

A round-bottomed flask was charged withtert-butyl-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate(1.7 g, 3.2 mmol) and 1,4-dioxane (20 mL) to give a brown solution. HCl(4 N in 1,4-dioxane, 4.05 mL, 16.2 mmol) was added and the mixture wasstirred at about 40° C. for about 3 h. The solvent was removed underreduced pressure. EtOAc (50 mL) and saturated aqueous NaHCO₃ (20 mL)were added. The resulting solid was collected by vacuum filtration anddried on the lyophilizer to give a grey solid (0.93 g). The layers ofthe filtrate were partitioned and the aqueous layer was extracted withEtOAc (3×40 mL). The organic layer was dried over anhydrous MgSO₄,filtered, and the solvent was removed under reduced pressure to give abrown residue (0.52 g). The material obtained was combined to give3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1, 2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopenta amine (1.45 g, 80% UV purity,84%): LC/MS (Table 2, Method a) R_(t)=1.76 min; MS m/z: 425 (M+H)⁺.

Step N:5-((1S,3R,4S)-3-Ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile and5-((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile

A 5 mL microwave reaction vial was charged with3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine(0.30 g, 0.71 mmol) in EtOH (2.0 mL) to give a brown suspension.5-Chloropyrazine-2-carbonitrile (0.118 g, 0.848 mmol, Ark Pharm) andDIEA (0.49 mL, 2.8 mmol) were added. The resulting suspension was heatedin a microwave at about 150° C. for about 1 h. The solvent was removedunder reduced pressure and EtOAc (50 mL) and water (20 mL) were added.The layers were partitioned and the organic layer was washed with brine(20 mL), dried over anhydrous MgSO₄, filtered, and the solvent wasremoved under reduced pressure to give crude.5-(−3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile(0.24 g, 40% UV purity, 0.18 mmol) that was dissolved in 1,4-dioxane (10ml) to give a brown solution. Saturated aqueous Na₂CO₃ (10 mL, 27 mmol)was added and the reaction mixture was stirred for about 96 h at about50° C. The reaction mixture was cooled to ambient temperature and EtOAc(50 mL) was added to the reaction mixture. The layers were separated andthe organic layer was washed with water (25 mL) and brine (25 mL), driedover anhydrous MgSO₄, filtered, and concentrated under reduced pressure.The crude material was purified by RP-HPLC (Table 2, Method m) to give a1:1 mixture of5-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrileand5-((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile(0.0025 g, 1.5%): LC/MS (Table 2, Method a) R_(t)=1.81 min; MS m/z: 374(M+H)⁺.

Example #193-((3R,4R)-3-(3H-Imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylpiperidin-1-yl)-3-oxopropanenitrile

Step A: 1-(Benzyloxycarbonyl)-4-methylpiperidine-3-carboxylic acid

4-Methylnicotinic acid hydrochloride (5.00 g, 36.5 mmol, ASDI) andplatinum (IV) oxide (0.35 g, 1.54 mmol) were shaken in AcOH (100 mL)under about 60 psi hydrogen for about 72 h at room temperature. Thereaction mixture was filtered through Celite® and concentrated underreduced pressure to give 4-methylpiperidine-3-carboxylic acidhydrochloride (7.4 g, contained residual AcOH) that was carried forwardwithout additional purification. To a portion of the acid (1.0 g, 4.92mmol) in 1,4-dioxane (10 mL) was added HCl (4 N in 1,4-dioxane, 4.0 mL,16 mmol). The mixture was stirred for about 10 min before adding Et₂O(10 mL). The precipitate was collected by vacuum filtration was washedwith Et₂O (5 mL) to give a solid (0.27 g). To the filtrate was added HCl(4 N in 1,4-dioxane, 4.0 mL, 16 mmol) and the mixture was concentratedunder reduced pressure to constant weight, while adding DCM (20 mL) tothe resulting residue to give a thick yellow oil (0.56 g). The twoportions were combined to give 4-methylpiperidine-3-carboxylic acidhydrochloride (0.83 g, 93%). To the acid (0.83 g, 4.6 mmol) was addedN-(benzyloxycarbonyloxy)succinimide (1.27 g, 5.08 mmol), Na₂CO₃ (1.71 g,16.2 mmol), and water: 1,4-dioxane (1: 1, 20 mL). The mixture wasstirred at room temperature for about 16 h and the organic solvent wasremoved under reduced pressure. The aqueous phase was neutralized by theaddition of 1N HCl. The solution was extracted with EtOAc (2×25 mL) andthe combined organic extracts were washed with brine and dried overanhydrous MgSO₄. The solution was filtered and concentrated underreduced pressure to give1-(benzyloxycarbonyl)-4-methylpiperidine-3-carboxylic acid (1.28 g,100%): LC/MS (Table 2, Method a) R_(t)=1.97 min; MS m/z: 278 (M+H)⁺.

Step B: Benzyl 3-(2-bromoacetyl)-4-methylpiperidine-1-carboxylate

To a solution of 1-(benzyloxycarbonyl)-4-methylpiperidine-3-carboxylicacid (1.28 g, 4.62 mmol) in DCM (40 mL) was added oxalyl chloride (0.930mL, 10.6 mmol) followed by the drop-wise addition of DMF (0.072 mL, 0.92mmol). The reaction mixture was stirred at room temperature overnight.The reaction mixture was concentrated to yield crude benzyl3-(chlorocarbonyl)-4-methylpiperidine-1-carboxylate (1.4 g, 4.7 mmol)which was dissolved in a mixture of Et₂O and MeCN (1:1, 16 mL) and addedto a solution of trimethylsilyldiazomethane (2 M in Et₂O, 9.47 mL, 18.5mmol) in Et₂O and MeCN (1:1, 16 mL) that was cooled to about 0° C. Theresulting mixture was stirred at about 0° C. for about 4 h and quenchedby a drop-wise addition of 48% aqueous HBr. The organic solvents wereremoved and the residue was purified by silica gel chromatographyeluting with a gradient of 10-40% EtOAc in heptane. Theproduct-containing fractions were concentrated under reduced pressure togive benzyl 3-(2-bromoacetyl)-4-methylpiperidine-1-carboxylate (0.78 g,47%): LC/MS (Table 2, Method a) R_(t)=2.50 min; MS m/z: 356 (M+H)⁺.

Step C: 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine

A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (78.0 g, 394 mmol, ArkPharm) in anhydrous DMF (272 mL) was added drop-wise over about 60 minto a stirred suspension of NaH (60% dispersion in mineral oil, 12.8 g,532 mmol) in anhydrous DMF (543 mL) at about 0-5° C. The brown reactionsolution was stirred for about 30 min at about 0-5° C. then a solutionof p-toluenesulfonyl chloride (94.0 g, 492 mmol) in anhydrous DMF (272mL) was added drop-wise over about 60 min at about 0-5° C. The reactionmixture was stirred at about 0-5° C. for about 1 h then allowed to warmto ambient temperature and stirred for about 18 h at ambienttemperature. The reaction mixture was poured slowly into ice water (6L), followed by the addition of aqueous 2.5 N NaOH (50.0 mL, 125 mmol).The precipitate was collected by filtration and stirred with cold water(3×200 mL). The solid was collected by filtration and dried to constantweight in a vacuum oven at about 55° C. to yield2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine: (134.6 g, 97%) as a palebeige solid: LC/MS (Table 2, Method d) R_(t)=1.58 min; MS m/z: 352/354(M+H)⁺.

Step D: Methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate

To a solution of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (5.00 g, 14.2mmol) in DMF (64 mL) were added dichlorobis(triphenylphosphine)palladium(0.60 g, 0.86 mmol), TEA (5.9 mL, 43 mmol), and MeOH (17 mL, 420 mmol).The reaction flask was fitted with a balloon filled with carbonmonoxide. The flask was evacuated and back-filled with carbon monoxidetwice and the mixture was heated at about 65° C. for about 3 h.Additional dichlorobis(triphenylphosphine) palladium (0.60 g, 0.86 mmol)was added and the flask was re-evacuated and back-filled with carbonmonoxide twice. The reaction mixture was heated at about 95° C. forabout 16 h under an atmosphere of carbon monoxide. The mixture wascooled to room temperature and poured into ice water (350 mL). Theresulting suspension was stirred for about 10 min and filtered. Thefilter cake was washed with water and the solid was lyophilized forabout 48 h to give methyl5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (5.0 g, 90% UV purity,95%) as a light brown solid:

LC/MS (Table 2, Method a) R_(t)=2.21 min; MS m/z: 332 (M+H)⁺.

Step E: 5-Tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acidhydrochloride

To a solution of methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate(2.5 g, 7.5 mmol) in 1,4-dioxane (50 mL) was added aqueous 6 N HCl (50.0mL, 1650 mmol) and the reaction mixture was stirred at about 65° C. forabout 5 h and at room temperature for about 72 h. The mixture wasre-heated to about 60° C. for about 3 h, and stirred at room temperaturefor about 48 h. The mixture was re-heated to about 65° C. for about 2 hand then cooled to room temperature. An insoluble bright yellow residuewas removed by filtration and the organic solvent was removed underreduced pressure to give a precipitate that was collected and dried togive 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid hydrochloride(1.92 g, 72%) as a tan solid: LC/MS (Table 2, Method a) R_(t)=1.48 min;MS m/z: 352 (M−H)⁻.

Step F: tert-Butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate

To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acidhydrochloride (1.92 g, 5.43 mmol) in t-BuOH (50 mL) was added TEA (1.67mL, 11.9 mmol) and diphenylphosphoryl azide (1.29 mL, 5.97 mmol). Thereaction mixture was heated at about 70° C. for about 8 h. The mixturewas cooled to room temperature and an insoluble residue was removed byfiltration. The filtrate was suspended in EtOAc and filtered. Thefiltrate was concentrated and the crude material was purified by silicagel chromatography eluting with a gradient of 17-100% EtOAc/heptane togive tert-Butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate as awhite solid (0.68 g). Chromatography also provided5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxamide (0.39 g, 1.23 mmol) thatwas reacted with lead tetraacetate (0.55 g, 1.2 mmol) in t-BuOH (25 mL)at room temperature for about 72 h then at reflux for about 4 h.Additional lead tetraacetate (1.36 g, 3.07 mmol) was added and themixture was heated at reflux for about 2 h. The insoluble residue wasremoved by filtration and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography asdescribed above to yield an additional portion of the desired product(0.18 g). The two crops were combined to give tert-butyl5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.86 g, 41%): LC/MS(Table 2, Method a) R_(t)=2.67 min; MS m/z: 389 (M+H)⁺.

Step G: Benzyl3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-methylpiperidine-1-carboxylate

To a suspension of NaH (60% dispersion in mineral oil, 0.088 g, 2.2mmol) in DMF at about 0° C. (10 mL) was added a solution of tert-butyl5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.86 g, 2.2 mmol, StepF) in DMF (10 mL) and the mixture was stirred at about 0° C. for about 1h. A solution of benzyl3-(2-bromoacetyl)-4-methylpiperidine-1-carboxylate (0.78 g, 2.2 mmol,Step B) in DMF (5 mL) was added drop-wise and the resulting mixture wasstirred at ambient temperature for about 16 h. The solvent was removedand the residue was partitioned between EtOAc and water (40 mL each).The organic phase was washed with brine (20 mL), dried over anhydrousMgSO₄, filtered, and concentrated under reduced pressure to give benzyl3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-methylpiperidine-1-carboxylate(1.45 g, 100%): LC/MS (Table 2, Method a) R_(t)=3.14 min; MS m/z: 662(M+H)⁺.

Step H: Benzyl4-methyl-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)acetyl)piperidine-1-carboxylate

Benzyl3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-methylpiperidine-1-carboxylate(1.45 g, 2.2 mmol) was stirred in HCl (4 N in 1,4-dioxane, 0.55 mL, 2.2mmol) at ambient temperature for about 90 min. The solvent was removedunder reduced pressure and the residue was neutralized with saturatedaqueous NaHCO₃. The aqueous phase was extracted with EtOAc (2×20 mL) andthe combined organic extracts were washed with brine (16 mL), dried overanhydrous MgSO₄, filtered, and concentrated to yield benzyl4-methyl-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)acetyl)piperidine-1-carboxylate(1.23 g, 100%) as a brown amorphous solid: LC/MS (Table 2, Method a)R_(t)=2.74 min; MS m/z: 562 (M+H)⁺.

Step I: Benzyl4-methyl-3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate

To the solution of benzyl4-methyl-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)acetyl)piperidine-1-carboxylate(1.2 g, 2.2 mmol) in 1,4-dioxane (15 mL) was added Lawesson's reagent(0.44 g, 1.1 mmol) and the mixture was heated at about 60° C. for about90 min. The solvent was removed under reduced pressure and the residuewas purified by silica gel chromatography eluting with a gradient of0-1.5% MeOH/DCM to yield benzyl4-methyl-3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate(0.93 g, 78%) as a yellow amorphous solid: LC/MS (Table 2, Method a)R_(t)=2.49 min; MS m/z: 544 (M+H)⁺.

Step J: Benzyl3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylpiperidine-1-carboxylate

To a solution of benzyl4-methyl-3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate(0.93 g, 1.7 mmol) in 1,4-dioxane (20 mL) was added aqueous NaOH (2 N,1.0 mL), and the resulting mixture was heated at about 90° C. for about80 min. The solvents were removed under reduced pressure and the residuewas treated with saturated aqueous NH₄Cl (26 mL) and extracted withEtOAc (2×30 mL). The combined organic extracts were washed with brine(20 mL), dried over anhydrous MgSO₄, filtered, and concentrated to yieldthe crude product as a brown amorphous solid. The material was purifiedby silica gel chromatography eluting with a gradient of 5-100% MeOH/DCMto give benzyl3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylpiperidine-1-carboxylate(0.55 g, 83%) as a yellow solid: LC/MS (Table 2, Method a) R_(t)=1.94min; MS m/z: 390 (M+H)⁺.

Step K:8-(4-Methylpiperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine

A mixture of benzyl3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylpiperidine-1-carboxylate(0.55 g, 1.4 mmol) and palladium on carbon (10%, 0.38 g, 0.36 mmol) inEtOH (25 mL) was hydrogenated at room temperature under an atmosphericpressure of hydrogen for about 20 h. The catalyst was removed byfiltration through a Celite® pad and the filtrate was concentrated invacuo to give8-(4-methylpiperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.30g, 83%) as a yellow amorphous solid: LC/MS (Table 2, Method a)R_(t)=0.93 min; MS m/z: 256 (M+H)⁺.

Step L:3-((3R,4R)-3-(3H-Imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylpiperidin-1-yl)-3-oxopropanenitrile

To a solution of8-(4-methylpiperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.30g, 1.2 mmol) in DMF (10 mL) were added DIEA (0.41 mL, 2.4 mmol) and EDC(0.68 g, 3.5 mmol). 2-Cyanoacetic acid (0.20 g, 2.4 mmol) was added andthe mixture was stirred at ambient temperature for about 14 h. Thesolvent was removed under reduced pressure and the residue waspartitioned between DCM and water (25 mL each). The organic phase waswashed with brine (20 mL), dried over anhydrous MgSO₄, filtered, andconcentrated under reduced pressure. Purification by silica gelchromatography eluting with a gradient of 0-8% MeOH in DCM gave theproduct as a white solid (0.29 g). Chiral separation (Table 3, Method10) of the material yielded material (Rt=22.5 min, or =positive) thatwas further purified by silica gel chromatography eluting with agradient of 0-8% MeOH in DCM to give3-((3R,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylpiperidin-1-yl)-3-oxopropanenitrile(0.04 g, 11%): LC/MS (Table 2, Method a) R_(t)=1.36 min; MS m/z: 323(M+H)⁺.

Example #207-(5-Methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine

Step A: 3-Iodo-5-methoxy-1-methyl-1H-indole

5-Methoxy-1H-indole (5.00 g, 34.0 mmol) in DMF (100 mL) was stirred withKOH (2.00 g, 35.7 mmol) for about 15 min then iodine (8.80 g, 34.7 mmol)was added. The mixture was stirred for about 30 min then NaH (60%dispersion in mineral oil, 1.63 g, 40.8 mmol) was added portion-wise.After stirring for about 15 min at ambient temperature, iodomethane(2.34 mL, 37.4 mmol) was added and the mixture was stirred for about 2h. The solvents were removed under reduced pressure and the mixture wasstirred with water (300 mL) for about 15 min. The slurry was treatedwith DCM (100 mL) and the layers were separated. The aqueous layer wasextracted with DCM (50 mL) and the combined organics were dried overanhydrous MgSO₄, filtered, and concentrated. The material was purifiedby silica gel chromatography eluting with DCM to give3-iodo-5-methoxy-1-methyl-1H-indole (9.48 g, 97%): ¹H NMR (400 MHz,DMSO-d₆ δ 7.48 (s, 1H), 7.38 (d, 1H), 6.86 (dd, 1H), 6.72 (d, 1H), 3.79(s, 3H), 3.76 (s, 3H); LC/MS (Table 2, Method a) R_(t)=2.50 min.

Step B:5-Bromo-3-((5-methoxy-1-methyl-1H-indol-3-yl)ethynyl)pyrazin-2-amine

A 500 mL round bottom flask was charged with NMP (120 mL) and3,5-dibromopyrazin-2-amine (9.00 g, 35.6 mmol). The mixture was degassedunder nitrogen and Pd(Ph₃P)₄ (3.29 g, 2.85 mmol) was added. The flaskwas wrapped with aluminum foil to protect it from light, and copper (I)iodide (0.678 g, 3.56 mmol), TEA (29.8 mL, 214 mmol) and(trimethylsilyl)acetylene (3.84 g, 39.1 mmol) were added. The mixturewas warmed to about 55° C. in an oil bath for about 1.5 h. The mixturewas cooled to ambient temperature and3-iodo-5-methoxy-1-methyl-1H-indole (9.76 g, 34.0 mmol), water (0.256mL, 14.2 mmol), NMP (1 mL) and DBU (37.5 mL, 249 mmol) were added. Themixture was stirred at ambient temperature for about 16 h. The mixturewas concentrated to remove volatiles and the mixture was diluted withwater (800 mL) and extracted with EtOAc (4×300 mL). The combined organiclayers were washed with water (600 mL). The emulsion which formed wasfiltered through Celite® to remove insoluble material. The filtratelayers were separated and the organic layer was dried over anhydrousMgSO₄, filtered, and concentrated to about 25 mL and purified by silicagel chromatography eluting with EtOAc. The product-containing fractionswere concentrated to give material, which was triturated with Et₂O (50mL), filtered, and washed with Et₂O (2×10 mL). The resulting solid wasdried to give 2.94 g of product. The filtrate obtained above wasconcentrated to about 6 mL and purified by silica gel chromatographyeluting with EtOAc to give a second batch of enriched material that wastriturated with Et₂O (20 mL) and filtered to give an additional 0.42 gof product. The two batches were combined to give5-bromo-3-((5-methoxy-1-methyl-1H-indol-3-yl)ethynyl)pyrazin-2-amine(3.36 g, 26%): LC/MS (Table 2, Method a) R_(t)=2.46 min; MS m/z: 357(M+H)⁺.

Step C:2-Bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine

5-Bromo-3-((5-methoxy-1-methyl-1H-indol-3-yl)ethynyl)pyrazin-2-amine(3.25 g, 9.10 mmol) in DMF (35 mL) was treated with NaH (60% dispersionin mineral oil, 0.36 g, 9.1 mmol). After about 5 h at ambienttemperature, the mixture was treated with another portion of NaH (60%dispersion in mineral oil, 0.036 g, 0.91 mmol) and stirred for about 16h. The mixture was concentrated and stirred with water (50 mL) and EtOAc(40 mL). The mixture was filtered and the solids were washed until aninsoluble tar remained. The filtrate layers were separated and theorganic layer was dried over anhydrous MgSO₄, filtered, andconcentrated. The material was dissolved in a minimum amount of warm DMFand purified by silica gel chromatography (120 g silica gel column)eluting with 95:5 DCM/MeOH. The product-containing fractions werecombined and concentrated to give an oil which was purified by silicagel chromatography (120 g silica column) eluting with EtOAc. Theproduct-containing fractions were combined and concentrated to give anoily residue which was triturated with EtOAc (20 mL) then filtered togive a yellow solid. The material was dried to give2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine(1.48 g, 45%): LC/MS (Table 2, Method a) R_(t)=2.50 min; MS m/z: 357(M+H)⁺.

Step D:2-Bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

2-Bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine(0.500 g, 1.40 mmol) in DMF (15 mL) was cooled to about 0° C. thentreated with NaH (60% dispersion in mineral oil, 0.112 g, 2.80 mmol).The mixture was stirred for about 15 min, SEM-Cl (0.372 mL, 2.10 mmol)was added, and the mixture was warmed to ambient temperature for about15 min. The mixture was concentrated and purified by silica gelchromatography (40 g silica column) eluting with DCM to give2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine(0.61 g, 89%): LC/MS (Table 2, Method a) R_(t)=3.88 min; MS m/z: 489(M+H)⁺.

Step E:(6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol

2-Bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine(0.815 g, 1.67 mmol), (E)-styrylboronic acid (0.272 g, 1.84 mmol,Combiblocks), Cs₂CO₃ (1.36 g, 4.18 mmol) and PdCl₂(PPh₃)₂ (0.070 g, 0.10mmol) in 1,4-dioxane (13 mL) and water (6.5 mL) was heated to about 70°C. overnight. The mixture was cooled and the solvents were concentratedunder reduced pressure. The material was partitioned between water (50mL) and EtOAc (60 mL) and the organic layer was dried over anhydrousMgSO₄, filtered, and concentrated to a foam (1.01 g). The material wasdissolved in 1,4-dioxane (15 mL) and water (3 mL), 2.5 wt % osmiumtetroxide in t-BuOH (0.84 ml, 0.067 mmol), and sodium periodate (1.43 g,6.69 mmol) were added. The mixture was stirred for about 1 h at ambienttemperature then 2.5 wt % osmium tetroxide in t-BuOH (0.84 mL, 0.067mmol) and water (3 mL) were added. The mixture was stirred for about 3 hthen diluted with water (50 mL). The mixture was extracted with EtOAc(50 mL and 25 mL volumes). The combined organic solutions were washedwith brine (30 mL), dried over anhydrous MgSO₄, filtered, andconcentrated to give an oil (0.97 g). The material was dissolved in1,4-dioxane (10 mL) and EtOH (2 mL) then treated with NaBH₄ (0.063 g,1.672 mmol) and stirred for about 30 min. The solvents were evaporatedand the material was partitioned between EtOAc (50 mL), water (20 mL),and saturated aqueous NaHCO₃ (20 mL). The layers were separated and theaqueous layer was extracted with EtOAc (2×20 mL). The combined organicsolutions were washed with brine (20 mL), dried over anhydrous MgSO₄,filtered, and concentrated under reduced pressure. The material waspurified by silica gel chromatography eluting with EtOAc to provide(6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol(0.63 g, 86%): LC/MS (Table 2, Method a) R_(t)=2.58 min; MS m/z: 439(M+H)⁺.

Step F:2-(Azidomethyl)-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

(6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol(0.63 g, 1.4 mmol) in DCM (10 mL) was treated with SOCl₂ (0.115 mL, 1.58mmol) and stirred for about 15 min at ambient temperature. The solventswere evaporated then sodium azide (0.280 g, 4.31 mmol) and DMF (5 mL)were added. The mixture was then stirred at ambient temperatureovernight. The solvent was evaporated and the residue was partitionedbetween water (30 mL) and EtOAc (25 mL). The aqueous layer was washedwith EtOAc (15 mL) then the combined organic solutions were dried overanhydrous MgSO₄, filtered, and concentrated to give2-(azidomethyl)-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine(0.58 g, 87%): LC/MS (Table 2, Method a) R_(t)=3.42 min; MS m/z: 464(M+H)⁺.

Step G:(6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine

2-(Azidomethyl)-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine(0.58 g, 1.3 mmol) in THF (15 mL) was treated with triphenylphosphine(0.335 g, 1.28 mmol) and water (0.150 mL, 8.33 mmol) then heated toabout 70° C. for about 2 h. The mixture was cooled then concentrated invacuo. The material was purified by silica gel chromatography elutingwith 9:1 DCM/MeOH containing 2.5 vol % 37 wt %. aqueous ammoniumhydroxide to give(6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine(0.37 g, 68%): LC/MS (Table 2, Method a) R_(t)=2.11 min; MS m/z: 438(M+H)⁺.

Step H:N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)acetamide

(6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine(0.185 g, 0.423 mmol) in THF (5 mL) was treated with pyridine (0.044 mL,0.55 mmol) and acetic anhydride (0.044 mL, 0.47 mmol). The mixture wasstirred for about 5 min at ambient temperature and treated with AcOH(0.024 mL, 0.42 mmol). The mixture was diluted with EtOAc (20 mL) andwashed with water (15 mL) and brine (10 mL). The organic solution wasdried over anhydrous MgSO₄, filtered, and concentrated to giveN-((6-(5-methoxy-1-methyl-H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-H-3-pyrazin-2-yl)methyl)acetamide(0.202 g, 100%): LC/MS (Table 2, Method a) R_(t)=2.63 min; MS m/z: 480(M+H)—.

Step I:N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)acetamide

N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)acetamide(0.200 g, 0.417 mmol) in DMF (10 mL) was treated with ethylenediamine(0.90 mL, 13 mmol) and TBAF (1 M in THF, 1.7 mL, 1.7 mmol). The mixturewas heated to about 85° C. for about 90 min then cooled and concentratedunder reduced pressure. The material was stirred with water (20 mL) forabout 16 h, Et₂O (10 mL) was added, and stirring was continued for about15 min. The slurry was filtered and the solid collected was dried. Thefiltrate was extracted with EtOAc (2×25 mL) then the combined organicsolutions were dried over anhydrous MgSO₄, filtered, and concentrated togive material, which was combined with the previously collected solid.The material was triturated with EtOAc (5 mL) and filtered to give asolid. The filtrate was purified by silica gel chromatography elutingwith DCM/MeOH (9:1) to give an additional amount of product which wascombined with the solid obtained from the EtOAc trituration to giveN-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)acetamide(0.108 g, 74%): LC/MS (Table 2, Method a) R_(t)=1.91 min; MS m/z: 350.2(M+H)—.

Step J:7-(5-Methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine

N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)acetamide(0.108 g, 0.309 mmol) in 1,4-dioxane (6 mL) was treated with Lawesson'sReagent (0.075 g, 0.19 mmol) and heated to about 85° C. for about 30min. The mixture was cooled briefly then another portion of Lawesson'sReagent (0.075 g, 0.19 mmol) was added. The mixture was heated to about85° C. for about 30 min. The mixture was cooled to ambient temperaturethen mercuric acetate (0.10 g, 0.31 mmol) was added. After about 15 minanother portion of mercuric acetate (0.10 g, 0.31 mmol) was added. Themixture was stirred for about 15 min then diluted with EtOAc (50 mL).The mixture was filtered and the cake was washed with EtOAc (2×25 mL).The filtrate was evaporated (and the residue set aside), and the solidswere dried and triturated with DCM (20 mL). The solids were collected byfiltration and washed with DCM (25 mL). The filtrate was concentratedand combined with the set-aside residue obtained from the EtOAcfiltration. The filter cake was dissolved in DMF (1.2 mL) and purifiedby silica gel chromatography (10 g column) eluting with 95:5 DCM/MeOH.The product-containing fractions were combined with the filtrates fromthe EtOAc and DCM triturations, concentrated, and the combined materialwas purified by silica gel chromatography (10 g column) eluting with95:5 DCM/MeOH. The product-containing fractions were combined. Thesilica columns were flushed with DMF (40 mL each) and allproduct-containing fractions were combined with those previouslycollected and the solvents were removed under reduced pressure. Theresidue was triturated with about MeOH (5 mL) and filtered. The filtercake was triturated with water (40 mL) and 37 wt % ammonium hydroxide (3mL) and extracted with EtOAc (5×50 mL). The organic extracts werecombined and washed with brine (25 mL), dried over anhydrous MgSO₄,filtered, and concentrated to give a solid (0.056 g). The material wastriturated with MeOH (5 mL). The solid was collected by filtration thendried to give7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinethat contained 5 weight % MeOH (0.037 g, 36%): LC/MS (Table 2, Method a)R_(t)=1.94 min; MS m/z: 332 (M+H), ¹H NMR (400 MHz, DMSOd₆) δ 12.19 (s,1H), 8.50 (s, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.45 (dd, J=14.8, 5.52Hz, 2H), 7.03 (d, J=2.07 Hz, 1H), 6.92 (dd, J=8.88, 2.25 Hz, 1H), 3.87(s, 3H), 3.83 (s, 3H), 2.95 (s, 3H).

Example #217-(5-Methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine

Step A:N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)formamide

(6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine(0.095 g, 0.22 mmol, Example #20, Step G) in ethyl formate (4.4 mL, 54.0mmol) was heated at about 60° C. in an oil bath for about 45 min. Themixture was cooled and evaporated to giveN-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)formamide(0.10 g, 100%): LC/MS (Table 2, Method a) R_(t)=2.65 min; MS m/z: 466(M+H)⁺.

Step B:7-(5-Methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine

N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)formamide(0.10 g, 0.22 mmol) in 1,4-dioxane (4 mL) was treated with Lawesson'sReagent (0.053 g, 0.13 mmol) and heated to about 80° C. in an oil bathfor about 15 min. The mixture was cooled and mercuric acetate (0.073 g,0.23 mmol, Fluka) was added. The mixture was stirred for about 30 min atambient temperature and another portion of mercuric acetate (0.073 g,0.228 mmol, Fluka) was added and stirring was continued for about 2 h atambient temperature. The mixture was diluted with EtOAc (20 mL) andfiltered. The solvent was evaporated under reduced pressure then thematerial was purified by silica gel chromatography eluting with DCM/MeOH(95:5). The material obtained after concentration of theproduct-containing fractions was further purified by silica gelchromatography eluting with EtOAc to give7-(5-methoxy-5-methyl-5H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine(0.048 g, 49%): LC/MS (Table 2, Method a) R_(t)=3.16 min; MS m/z: 448(M+H)⁺.

Step C:7-(5-Methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine

7-(5-Methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine(0.048 g, 0.11 mmol) in DMF (4 mL) was treated with ethylenediamine(0.22 mL, 3.3 mmol) and heated to about 85° C. for about 5 min. Thesolution was cooled and TBAF (1 M in THF, 0.11 mL, 0.11 mmol) was added.The solution was re-heated to about 85° C. for about 30 min. The mixturewas cooled to ambient temperature and another portion of the TBAF (1 Min THF, 0.054 mL, 0.054 mmol) was added and heating was continued forabout 1.5 h. The solution was cooled and the material was purified bypreparative RP-HPLC (Table 2, Method 1). The product-containingfractions were concentrated to remove MeCN then basified with saturatedaqueous NaHCO₃ and extracted with EtOAc (2×10 mL). The combined organicsolutions were dried over anhydrous MgSO₄, filtered, and concentrated.Trituration of the solid with heptane (5 mL) then collection byfiltration gave7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine(0.028 g, 8%): LC/MS (Table 2, Method a) R_(t)=1.91 min; MS m/z: 318.1(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆ δ 12.18 (s, 1H), 8.77 (s, 1H), 8.59 (s,1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.43 (d, J=8.9Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 6.92 (dd, J=8.90, 2.36 Hz, 1H), 3.88(s, 3H), 3.82 (s, 3H).

Example #227-(5-Methoxy-1-methyl-1H-indol-3-yl)-1-phenyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine

Step A:N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)benzamide

(6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine(0.095 g, 0.28 mmol, Example #20, Step G) in THF (5 mL) was treated withpyridine (0.026 ml, 0.33 mmol) and benzoyl chloride (0.033 ml, 0.28mmol). The mixture was stirred for about 20 min at about 60° C. andcooled to ambient temperature, diluted with aqueous Na₂CO₃ (15 mL), andextracted with EtOAc (20 mL). The organic solution was dried overanhydrous MgSO₄, filtered, and concentrated to giveN-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)benzamide(0.118 g, 100%): LC/MS (Table 2, Method d) R_(t)=1.64 min; MS m/z: 542(M+H)⁺.

Step B:7-(5-Methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine

N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)benzamide(0.118 g, 0.218 mmol) in 1,4-dioxane (3 mL) was treated with Lawesson'sReagent (0.070 g, 0.17 mmol) and was heated to about 80° C. in an oilbath for about 20 min. The mixture was cooled to ambient temperature andthen mercuric acetate (0.073 g, 0.23 mmol) was added. The mixture wasstirred for about 60 min at ambient temperature then another portion ofmercuric acetate (0.069 g, 0.22 mmol) was added and stirring wascontinued for about 20 min at ambient temperature. The mixture wasdiluted with EtOAc (20 mL) and then filtered. The filtrate wasconcentrated under reduced pressure and the material was purified bysilica gel chromatography eluting with EtOAc to give7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine(0.055 g, 48%): LC/MS (Table 2, Method d) R_(t)=1.91 min; MS m/z: 524(M+H)⁺.

Step C:7-(5-Methoxy-1-methyl-1H-indol-3-yl)-1-phenyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine

7-(5-Methoxy-1-methyl-1H-indol-3-yl)-1-phenyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine(0.054 g, 0.103 mmol) in DMF (3 mL) was treated with ethylenediamine(0.207 ml, 3.09 mmol) and TBAF (1 M in THF, 0.412 mL, 0.412 mmol). Thesolution was heated to about 90° C. for about 70 min. The mixture wascooled to ambient temperature and the mixture was diluted with EtOAc (10mL), washed with water (6 mL), dried over anhydrous MgSO₄, filtered, andconcentrated to give a yellow residue. The residue was purified bysilica gel chromatography eluting with 1-6% MeOH/DCM to provide a yellowsolid. The solid was triturated with heptane (2 mL) to provide7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-phenyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine(0.004 g, 10%): LC/MS (Table 2, Method a) R_(t)=2.26 min; MS m/z: 394(M+H)⁺.

TABLE 4 Examples found in Tables D.1 through II.2 Ex- ample # StructureD.1.2

D.1.3

D.1.4

E.1.2

E.1.3

E.1.4

E.1.5

F.1.2

F.1.3

G.1.2

G.1.3

G.1.4

G.1.5

G.1.6

G.1.7

G.1.8

G.1.9

G.1.10

G.1.11

G.1.12

G.1.13

G.1.14

G.1.15

G.1.16

G.1.17

G.1.18

G.1.19

G.1.20

G.1.21

G.1.22

G.1.23

G.1.24

G.1.25

G.1.26

G.1.27

G.1.28

G.1.29

G.1.30

G.1.31

G.1.32

G.1.33

G.1.34

G.1.35

G.1.36

G.1.37

G.1.38

G.1.39

H.1.2

H.1.3

H.1.4

H.1.5

H.1.6

H.1.7

H.1.8

H.1.9

H.1.10

H.1.11

H.1.12

H.1.13

H.1.14

H.1.15

H.1.16

H.1.17

H.1.18

H.1.19

H.1.20

H.1.21

H.1.22

H.1.23

H.1.24

H.1.25

H.1.26

H.1.27

H.1.28

H.1.29

H.1.30

H.1.31

H.1.32

H.1.33

H.1.34

H.1.35

H.1.36

H.1.37

H.1.38

H.1.39

H.1.40

H.1.41

H.1.42

H.1.43

H.1.44

H.1.45

H.1.46

H.1.47

H.1.48

H.1.49

H.1.50

H.1.51

H.1.52

H.1.53

H.1.54

H.1.55

H.1.56

H.1.57

H.1.58

H.1.59

H.1.60

H.1.61

H.1.62

H.1.63

H.1.64

H.1.65

H.1.66

H.1.67

H.1.68

H.1.69

H.1.70

H.1.71

H.1.72

H.1.73

H.1.74

H.1.75

H.1.76

H.1.77

H.1.78

H.1.79

H.1.80

H.1.81

H.1.82

H.1.83

H.1.84

H.1.85

H.1.86

H.1.87

H.1.88

H.1.89

H.1.90

H.1.91

H.1.92

H.1.93

H.1.94

H.1.95

H.1.96

H.1.97

H.1.98

H.1.99

H.1.100

H.1.101

H.1.102

H.1.103

H.1.104

H.1.105

H.1.106

H.1.107

H.1.108

H.1.109

I.1.2

I.1.3

I.1.4

I.1.5

I.1.6

I.1.7

I.1.8

I.1.9

I.1.10

J.1.2

J.1.3

J.1.4

K.1.2

K.1.3

K.1.4

K.1.5

K.1.6

L.1.2

L.1.3

L.1.4

L.1.5

L.2.1

L.2.2

L.3.1

L.3.2

L.3.3

L.3.4

L.3.5

L.3.6

L.3.7

L.3.8

L.3.9

L.4.1

L.4.2

L.4.3

L.4.4

L.4.5

L.4.6

L.4.7

L.5.1

L.5.2

L.6.1

M.1.2

M.1.3

N.1.2

N.1.3

N.1.4

N.1.5

N.1.6

N.1.7

N.1.8

N.1.9

N.1.10

N.1.11

N.1.12

N.1.13

N.1.14

N.1.15

N.1.16

N.1.17

N.1.18

N.2.1

N.2.2

N.2.3

N.2.4

N.2.5

N.2.6

N.2.7

N.2.8

N.2.9

N.2.10

N.2.11

N.3.1

N.3.2

N.3.3

N.3.4

N.3.5

N.4.1

N.4.2

N.4.3

N.4.4

N.4.5

N.4.6

N.5.1

O.1.2

O.1.3

O.1.4

O.1.5

O.1.6

O.1.7

O.2.1

O.2.2

O.2.3

O.3.1

O.3.2

O.3.3

O.4.1

O.5.1

O.6.1

O.7.1

O.8.1

II.1.1

II.1.2

II.1.3

II.1.4

II.1.5

II.1.6

II.1.7

II.1.8

II.1.9

II.1.10

II.1.11

II.1.12

II.1.13

II.1.14

II.2.1

II.2.2

II.2.3

II.2.4

Preparation #29:(3R)-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine

Step A: (3R)-3-(Dibenzylamino)-N-methoxy-N-methylcyclopentanecarboxamide

Hydrogen chloride gas was bubbled through a solution of(1S,3R)-3-aminocyclopentanecarboxylic acid (4.22 g, 32.7 mmol, Peptech)in MeOH (15 mL) for about 5 min. The resulting mixture was stirred atabout 50° C. for about 6 h and then at room temperature for about 16 h.The solvent was removed under reduced pressure and the residue wassuspended in MeCN (30 mL). The precipitate was collected by filtrationand dried in vacuo to yield, (3R)-methyl 3-aminocyclopentanecarboxylatehydrochloride (3.1 g, 53%) as a white solid. Et₂O (120 mL) was added tothe filtrate and the precipitate was collected by vacuum filtration togive additional (3R)-methyl 3-aminocyclopentanecarboxylate hydrochloride(1.1 g, 19%) which was combined with the product above to give(3R)-methyl 3-aminocyclopentanecarboxylate hydrochloride (4.2 g, 72%total) that was used without further purification. A portion of thisester (3.05 g, 17.0 mmol) was dissolved in DMF (15 mL), followed by theadditional of benzyl bromide (5.80 g, 34.0 mmol) and K₂CO₃ (7.27 g, 52.6mmol). The mixture was stirred at room temperature about 16 h, filtered,and the filtrate was concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography eluting with agradient of 5-35% EtOAc in heptane to give (3R)-methyl3-(dibenzylamino)cyclopentanecarboxylate (3.52 g, 64%) as a colorlessoil that was used directly. A portion of this material (1.18 g, 3.65mmol) was combined with O,N-dimethylhydroxylamine hydrochloride (1.07 g,10.9 mmol) in THF (40 mL) at about −25° C., followed by the drop-wiseaddition of LHMDS (1 M in THF, 14.6 mL, 14.6 mmol). The mixture wasstirred at about 0° C. for about 1 h. The mixture was re-cooled to about−25° C. and O,N-dimethylhydroxylamine hydrochloride (0.50 g, 5.1 mmol)was added, followed by the drop-wise addition of additional LHMDS (1 Min THF, 14.6 mL, 14.6 mmol). The reaction mixture was stirred at about0° C. for about 1 h and was quenched by the drop-wise addition of water(10 mL). The organic solvent was removed under reduced pressure. DCM (60mL) was added and the layers were separated. The organic phase waswashed with brine, concentrated under reduced pressure, and purified bysilica gel chromatography eluting with a gradient of 5-35% EtOAc inheptane to yield(3R)-3-(dibenzylamino)-N-methoxy-N-methylcyclopentanecarboxamide (1.01g, 79%) as a colorless oil: LC/MS (Table 2, Method a) R_(t)=2.08 min; MSm/z: 353 (M+H)⁺.

Step B: (3R)-3-(Dibenzylamino)cyclopentanecarbaldehyde

A solution of(3R)-3-(dibenzylamino)-N-methoxy-N-methylcyclopentanecarboxamide (3.34g, 9.48 mmol) in THF (70 mL) was cooled to about −78° C., followed bythe drop-wise addition of DIBAL-H (1.0 M in hexanes, 9.48 mL, 9.48mmol). The reaction mixture was stirred at about −78° C. for about 1 h,and was quenched by drop-wise addition of saturated aqueous sodiumpotassium tartrate. The resulting mixture was stirred at roomtemperature for about 1 h. The solvent was removed under reducedpressure and the aqueous layer was extracted with EtOAc (100 mL). Theorganic layer was washed with brine, dried over anhydrous MgSO₄, andconcentrated in vacuo. The residue was purified by chromatography onneutral alumina eluting with a gradient of 0-20% EtOAc in heptane toyield (3R)-3-(dibenzylamino)cyclopentanecarbaldehyde (1.63 g, 75%) as acolorless oil: LC/MS (Table 2, Method a) R_(t)=2.03 min; MS m/z: 294(M+H)⁺.

Step C:(5-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3R)-3-(dibenzylamino)cyclopentyl)methanol

A solution of5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.23 g,2.83 mmol, Adesis) in THF (10 mL) was cooled to about −78° C. and n-BuLi(1.6 M in hexanes, 2.3 mL, 3.7 mmol) was added drop-wise while keepingthe temperature below about −70° C. The mixture was stirred for about 40min, and a solution of (3R)-3-(dibenzylamino)cyclopentanecarbaldehyde(0.83 g, 2.8 mmol, Step B) in THF (3 mL) was added drop-wise, and theresulting mixture was stirred at about −75° C. for about 2 h. Thereaction mixture was quenched by a drop-wise addition of saturatedaqueous NH₄Cl (20 mL), and the organic solvent was removed under reducedpressure. The aqueous mixture was extracted with EtOAc (25 mL) and theorganic layer was washed with brine (20 mL) and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with a gradient of 0-20% EtOAc in heptane to yield(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3R)-3-(dibenzylamino)cyclopentyl)methanol(1.14 g, 67%): LC/MS (Table 2, Method a) R_(t)=3.31 min; MS m/z: 602(M+H)⁺.

Step D:(5-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3R)-3-(dibenzylamino)cyclopentyl)methanone

A solution of(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3R)-3-(dibenzylamino)cyclopentyl)methanol(1.14 g, 1.89 mmol) in DCM (50 mL) was cooled to about 0° C. Dess-Martinperiodinane (2.41 g, 5.68 mmol) was added and the reaction mixture wasstirred at about 0-10° C. for about 3 h. The mixture was quenched by adrop-wise addition of aqueous sodium sulfite (1 M, 20 mL), and theorganic solvent was removed under reduced pressure. The aqueous layerwas extracted with EtOAc (2×25 mL), and the combined organic extractswere washed with aqueous NaOH (1 N, 3×20 mL), brine, dried overanhydrous MgSO₄, filtered, and concentrated. The residue was purified bysilica gel chromatography eluting with a gradient of 0-20% EtOAc inheptane to yield(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3R)-3-(dibenzylamino)cyclopentyl)methanone(0.68 g, 60%) as a yellow amorphous solid: LC MS (Table 2, Method a)R_(t)=1.65 min; MS m/z: 442 (M+H)⁺.

Step E:(3R)-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine

A mixture of(5-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3R)-3-(dibenzylamino)cyclopentyl)methanone(1.5 g, 2.5 mmol), hydrazine (0.24 mL, 7.5 mmol), and AcOH (0.14 mL, 2.5mmol) in EtOH (40 mL) was heated to reflux for about 8 h and at about90° C. for about 16 h. The solvent was removed in vacuo and the residuewas partitioned between saturated aqueous NaHCO₃ (50 mL) and EtOAc (50mL). The organic phase was separated and washed with brine (40 mL),dried over anhydrous MgSO₄, filtered, and concentrated to yield crude(3R)-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine(1.14 g, 100%) as a yellow amorphous solid that was used withoutpurification. To a solution of the hydrazone (1.14 g, 2.5 mmol) in NMP(4 mL) were added sodium tert-butoxide (0.58 g, 6.0 mmol), palladium(II) acetate (0.0056 g, 0.025 mmol), and CyPFt-Bu (0.014 g, 0.025 mmol).The mixture was heated at about 140° C. for about 15 min in a microwave,and the solvent was removed under reduced pressure. The residue waspartitioned between EtOAc (25 mL) and water (25 mL), and the organicsolution was washed with brine, dried over anhydrous MgSO₄, filtered,and concentrated to give crude(3R)—N,N-dibenzyl-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine(1.05 g, 100%) as a dark brown solid that was used without purification.To a solution of the protected amine (1.05 g, 2.5 mmol) in MeOH (15 mL)was added Pd(OH)₂ (0.23 g, 1.6 mmol) and ammonium formate (1.58 g, 25.0mmol). The mixture was heated at about 65° C. for about 1 h. Thecatalyst was removed by filtration and the filtrate was concentratedunder reduced pressure to give crude(3R)-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine(0.60 g, 100%) as a brown solid that was used without purification:LC/MS (Table 2, Method a) R=1.12 min; MS m/z: 242 (M+H)⁺.

Preparation #30:(1S)-3-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine

Step A: (3S)-Methyl 3-(dibenzylamino)cyclopentanecarboxylate

Hydrogen chloride gas was bubbled through a solution of(1R,3S)-3-aminocyclopentanecarboxylic acid (5.00 g, 38.7 mmol, Peptech)in MeOH (100 mL) for about 15 min to give a tan solution, and thereaction mixture was stirred at ambient temperature for about 24 h. Thesolvent was removed under reduced pressure to give (3S)-methyl3-aminocyclopentanecarboxylate (5.5 g, 25.5 mmol, 66%) which wasdissolved in DMF (100 mL) and then K₂CO₃ (17.6 g, 127 mmol) and(bromomethyl)benzene (6.05 mL, 50.9 mmol) were added. The reactionmixture was stirred overnight at ambient temperature. The solid wascollected by filtration and washed with DMF (100 mL). The filtrate wasconcentrated under high vacuum and the crude material was purified bysilica gel chromatography eluting with 10% EtOAc in heptane to give(3S)-methyl 3-(dibenzylamino)cyclopentanecarboxylate (7.3 g, 89%) as ayellow oil: LC/MS (Table 2, Method a) R_(t)=2.97 min; MS m/z: 324(M+H)⁺.

Step B: (3S)-3-(Dibenzylamino)cyclopentanecarbaldehyde

A round bottom flask was charged with (3S)-methyl3-(dibenzylamino)cyclopentanecarboxylate (7.3 g, 23 mmol) in THF (154mL) to give a colorless solution. The solution was cooled to about −25°C. followed by the addition of N,O-dimethylhydroxylamine hydrochloride(5.95 g, 61.0 mmol). A solution of LHMDS (1 M in THF, 84 mL, 84 mmol)was added drop-wise and the reaction was stirred for about 1 h at about0° C. The reaction mixture was re-cooled to about −25° C. and additionalN,O-dimethylhydroxylamine hydrochloride (0.5 g, 5 mmol) and 10 mL ofLHMDS (1 M in THF, 10 mL, 10 mmol) were added. The reaction mixture wasstirred at about 0° C. for about 1 h. Analysis of the reaction mixtureby LC/MS indicated that starting material still remained, and themixture was re-cooled to about −25° C. and N,O-dimethylhydroxylaminehydrochloride (2.0 g, 20 mmol) and LHMDS (1 M in THF, 20 mL, 20 mmol)were added. The reaction mixture was stirred at about 0° C. for about 1h. This re-cooling and addition sequence was repeated once more with theaddition of N,O-dimethylhydroxylamine hydrochloride (1.5 g, 15 mmol) andLHMDS (1 M in THF, 40 mL, 40 mmol). After stirring at about 0° C. forabout 1 h, water (50 mL) was added drop-wise. The organic solvent wasremoved under reduced pressure, and EtOAc (200 mL) was added. The layerswere partitioned and the organic layer was washed with water (250 mL)and brine (125 mL), dried over anhydrous MgSO₄, filtered, and thesolvent was removed under reduced pressure to give a brown oil. Thecrude product was purified by silica gel chromatography (120 g column)eluting with 20% EtOAc in heptane to give(3S)-3-(dibenzylamino)-N-methoxy-N-methylcyclopentanecarboxamide (6.86g, 19 mmol, 86%) which was dissolved in THF (100 mL) and cooled to about−78° C. DIBAL-H (1.0 M in hexanes, 21.2 mL, 21.2 mmol) was addeddrop-wise to the solution over about 15 min. The reaction solution wasstirred at about −78° C. for about 1 h. Saturated aqueous potassiumsodium tartrate (25 mL) was added drop-wise at about −78° C. and thereaction mixture was stirred at ambient temperature for about 1 h. Theorganic solvent was removed under reduced pressure, EtOAc (100 mL) wasadded, and the layers were separated. The aqueous layer was extractedwith EtOAc (2×25 mL). The combined organic layers were washed with brine(3×50 mL), dried over anhydrous MgSO₄, filtered, and the solvent wasremoved under reduced pressure to give a yellow oil. The crude materialwas purified by silica gel chromatography eluting with 10% EtOAc inheptane to give (3S)-3-(dibenzylamino)cyclopentanecarbaldehyde (5.6 g,100%): LC/MS (Table 2, Method a) R_(t)=2.26 min; MS m/z: 294 (M+H)⁺.

Step C:(5-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3S)-3-(dibenzylamino)cyclopentyl)methanol

A round-bottomed flask was charged with5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.5 g,8.05 mmol, Adesis) in THF (161 mL) to give a colorless solution. Thesolution was cooled to about −78° C. and n-BuLi (1.6 M in hexanes, 6.54mL, 10.46 mmol) was added drop-wise over about 15 min. After addition ofthe n-BuLi solution was complete,(3S)-3-(dibenzylamino)cyclopentanecarbaldehyde (2.48 g, 8.45 mmol) inTHF (10 mL) was added drop-wise over about 5 min. The reaction mixturewas stirred for about 4 h at about −78° C. Saturated aqueous NH₄Cl (40mL) was added slowly and the mixture was stirred for about 5 min. Theorganic solvent was removed under reduced pressure and EtOAc (100 mL)was added. The layers were separated and the organic layer was washedwith brine (3×50 mL), dried over MgSO₄, filtered, and the solvent wasremoved under reduced pressure to give a yellow oil that was purified bysilica gel chromatography eluting with a gradient of 5-10% EtOAc inheptane. The product containing fractions were combined and concentratedto give(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3S)-3-(dibenzylamino)cyclopentyl)methanol(3.5 g, 72%): LC/MS (Table 2, Method n) R_(t)=2.97 min; MS m/z: 603(M+H)⁺.

Step D:(5-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3S)-3-(dibenzylamino)cyclopentyl)methanone

A round-bottomed flask was charged with(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3S)-3-(dibenzylamino)cyclopentyl)methanol(3.51 g, 5.83 mmol) in DCM (104 mL) to give a yellow solution. Thesolution was cooled to about 0° C. Dess-Martin periodinane (7.41 g,17.48 mmol) was added and the mixture was stirred at about 0° C. forabout 2 h then at ambient temperature for about 3 h. The reactionmixture was then re-cooled to about 0° C. and saturated aqueous sodiumsulfite (50 mL) was added slowly. The organic solvent was removed underreduced pressure. EtOAc (100 mL) was added and the layers werepartitioned. The organic layer was washed with saturated aqueous NaHCO₃(2×20 mL) and brine (3×50 mL), dried over anhydrous MgSO₄, filtered, andthe solvent was removed under reduced pressure to give a brown oil. Thecrude material was purified by silica gel chromatography eluting with 5%EtOAc in heptane. A second purification by neutral aluminachromatography eluting with a step-wise gradient of 0-100% EtOAc inheptane yielded(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3S)-3-(dibenzylamino)cyclopentyl)methanone(1.7 g, 50%) as a yellow oil: LC/MS (Table 2, Method n) R_(t)=3.90 min;MS m/z: 601 (M+H)⁺.

Step E:(1S)—N,N-Dibenzyl-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine

A round-bottomed flask was charged with(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3S)-3-(dibenzylamino)cyclopentyl)methanone(1.65 g, 2.76 mmol) in n-butanol (44.4 mL) to give a yellow solution.Hydrazine (0.259 mL, 8.27 mmol) and AcOH (0.16 mL, 2.8 mmol) were added.The reaction mixture was fitted with a Dean Stark trap containingpre-activated 3 Å molecular sieves and n-BuOH. The reaction mixture washeated at about 140° C. for about 6 h. Hydrazine (0.26 mL, 8.3 mmol) andAcOH (0.16 mL, 2.8 mmol) were added and the reaction mixture was heatedat about 140° C. for about 6 h. The reaction mixture was cooled to roomtemperature and the solvent was removed under reduced pressure. EtOAc(50 mL) and saturated aqueous NaHCO₃ (20 mL) were added and the layerswere separated. The organic layer was washed with additional saturatedaqueous NaHCO₃ (2×50 mL) and brine (3×50 mL), dried over anhydrousMgSO₄, filtered, and the solvent was removed under reduced pressure togive a brown syrup.(1S)—N,N-Dibenzyl-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine(1.4 g) was dried for about 48 h under high vacuum and used directly.Four 5 mL microwave reaction vials were each charged with(1S)—N,N-dibenzyl-3-((5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(hydrazono)methyl)cyclopentanamine(0.35 g, 0.78 mmol) in NMP (1.2 mL) to give an orange solution. KOt-Bu(0.18 g, 1.8 mmol) was added followed by addition of a stock solution ofPd(OAc)₂ (0.008 mmol) and(R)-1-[(S)-2-(dicyclohexylphosphino)-ferrocenyl]ethyl-di-tert-butylphosphine(0.008 mmol) in NMP (0.1 M in each substrate, 0.080 mL) into each vial.The vials were capped, and the solutions were heated in a CEM microwaveat about 140° C. for about 15 min (250 psi maximum pressure, 1 min ramp,300 max watts). An additional portion of the catalyst-ligand solution(0.0008 mmol of each, 0.080 mL) was added to the reaction solutions andthe mixtures were heated in the microwave for about an additional 30 minat about 140° C. The reaction mixtures were combined and the solvent wasremoved under reduced pressure. The residue was dissolved in EtOAc andMeOH and filtered through a pad of Celite® pad while washing with EtOAcand MeOH. The filtrate was concentrated under reduced pressure and theresidue was dissolved in DCM (100 mL) and washed with saturated aqueousNH₄Cl (3×50 mL) and brine (2×50 mL), dried over MgSO₄, filtered, andsolvent was removed under reduced pressure to give(1S)—N,N-dibenzyl-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine(1.2 g, 73%) as a brown syrup: (Table 2, Method n) R_(t)=1.11 min; MSm/z: 422 (M+H)⁺.

Step F:(1S)-3-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine

A round-bottomed flask was charged with(1S)—N,N-dibenzyl-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine(1.11 g, 2.65 mmol) in MeOH (15.8 mL) to give a brown solution. Ammoniumformate (1.67 g, 26.5 mmol) and Pd(OH)₂—C (0.93 g, 1.3 mmol) were added.The suspension was heated at about 65° C. for about 90 min. followed bythe addition of ammonium formate (0.84 g, 13.3 mmol). The mixture wasstirred at about 65° C. for about 1 h. Additional ammonium formate (1.67g, 26.5 mmol) was added and the mixture was stirred at about 65° C. forabout 1.5 h. Additional Pd(OH)₂—C (0.7 g, 1.0 mmol) was added and themixture was stirred at about 65° C. for about 1 h. The mixture wascooled to about 0° C. and filtered through a pad of Celite® whilewashing with MeOH (175 mL). The filtrate was concentrated under reducedpressure and the residue was dissolved in water and washed with EtOAc.The aqueous layer concentrated under reduced pressure to afford(1S)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanmine (0.46 g, 72%) as a brown syrup: (Table 2, Method a) R_(t)=1.07 min;MS m/z: 242 (M+H)⁺.

Preparation #31:5-Methoxy-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

5-Methoxy-1H-indole (5.15 g, 35.0 mmol) in DMF (100 mL) was stirred withKOH (2.06 g, 36.7 mmol) at room temperature for about 15 min then iodine(9.06 g, 35.7 mmol) was added. The mixture was stirred at roomtemperature for about 30 min followed by the portion-wise addition ofNaH (60% dispersion in mineral oil, 1.67 g, 42.0 mmol). After stirringfor about 15 min at room temperature, iodomethane (2.40 mL, 38.5 mmol)was added and the mixture was stirred for about 15 min. The solventswere removed under reduced pressure and the mixture was stirred withwater (300 mL) for about 15 min. The slurry was treated with DCM (100mL) and the layers were separated. The aqueous layer was extracted withDCM (30 mL) and the combined organic layers were washed with water (100mL), dried over anhydrous MgSO₄, filtered, and concentrated in vacuo togive crude 3-iodo-5-methoxy-1-methyl-1H-indole (9.90 g, 34.5 mmol, 99%)which was used directly. A round bottom flask was charged with3-iodo-5-methoxy-1-methyl-1H-indole (9.90 g, 34.5 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (1.408 g, 1.724 mmol), TEA (33.6 mL, 241mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (28.7 g, 224 mmol) and1,4-dioxane (200 mL). The reaction mixture was heated at about 100° C.for about 40 min, cooled to room temperature, and concentrated in vacuo.The material was stirred with EtOAc (300 mL), filtered, and the filtercake was washed with EtOAc (100 mL). The filtrate was concentrated invacuo and the residue purified by silica gel chromatography (120 gcolumn) eluting with 25% EtOAc in heptane to give5-methoxy-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(3.70 g, 37%): LC/MS (Table 2, Method d) R_(t)=2.68 min; MS m/z: 288.2(M+H)⁺.

Example #231-Cyclohexyl-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

Step A: (5-Chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanol

To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (3.0g, 16 mmol, Adesis) in THF (100 mL) at about 0° C. was addedcyclohexylmagnesium chloride (2 M in Et₂O, 22.8 mL, 45.7 mmol). Thereaction mixture was stirred at ambient temperature for about 2 h, thenadditional cyclohexylmagnesium chloride (2 M in Et₂O, 8.3 mL, 16.6 mmol)was added. The reaction mixture was stirred at ambient temperature forabout 16 h. Water (10 mL) was added to quench the reaction and thevolatiles were removed under reduced pressure. The product was extractedinto DCM (3×20 mL) and the combined organic phases were dried overanhydrous MgSO₄ and filtered. The solvent was removed under reducedpressure and the crude material was purified by chromatography oversilica gel using a gradient of 10 to 45% EtOAc in heptane as the eluentto provide (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanolas an off white solid (1.97 g, 45%): LC/MS (Table 2, Method a)R_(t)=2.32 min; MS m/z: 265 and 267 (M+H)⁺.

Step B: (5-Chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone

To a suspension of(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanol (1.97 g,7.44 mmol) in DCM (39.4 mL) at about 0° C. was added Dess-Martinperiodinane (9.47 g, 22.3 mmol). The reaction mixture was stirred atambient temperature for about 4 h then quenched by the addition ofsaturated aqueous Na₂SO₃ (125 mL). To control the resulting exothermicreaction, the reaction flask was cooled down in an ice bath during theaddition. The product was extracted into DCM (3×40 mL) and the combinedorganic extracts were washed with aqueous NaOH (2 N, 100 mL). Theorganic phase was dried over anhydrous MgSO₄, filtered, and the solventwas removed under reduced pressure to provide(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone as anoff-white solid (1.75 g, 90%); LC/MS (Table 2, Method a) R_(t)=2.61 min;MS m/z: 263 and 265 (M+H)⁺. The material was used directly in the nextstep without further purification.

Step C:5-Chloro-4-(cyclohexyl(hydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine

A mixture of(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone (0.720 g,2.74 mmol), anhydrous hydrazine (0.430 mL, 13.7 mmol) and AcOH (0.025mL, 0.44 mmol) in EtOH (40 mL) was heated at reflux for about 20 h.During this time, water was removed from the reaction mixture via theuse of a Dean-Stark trap. The reaction mixture was cooled to ambienttemperature, the volatiles were removed under reduced pressure and theresidue was partitioned between water (29 mL) and EtOAc (30 mL). Theorganic layer was dried over anhydrous MgSO₄, filtered, and the solventevaporated under reduced pressure. The crude material was purified bysilica gel chromatography using a gradient of 10 to 50% EtOAc in heptaneas the eluent to provide5-chloro-4-(cyclohexyl(hydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine as anoff-white solid (0.37 g, 48%); LC/MS (Table 2, Method o) R_(t)=2.22 min;MS m/z: 277 and 279 (M+H)⁺.

Step D: 1-Cyclohexyl-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

A mixture of5-chloro-4-(cyclohexyl(hydrazono)methyl)-1H-pyrrolo[2,3-h]pyridine(0.125 g, 0.452 mmol), sodium tert-butoxide (0.104 g, 1.08 mmol),palladium acetate (0.001 g, 0.0045 mmol) and(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (0.0025 g, 0.0045 mmol) was heated in N-methyl-2-pyrrolidinone(2 mL) at about 160° C. in a CEM Discover microwave for about 30 min.The insoluble residue was removed by filtration and the filtrate wassubjected to purification by preparative RP-HPLC (Table 2, Method h) toyield 1-cyclohexyl-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine as awhite solid (0.036 g, 33%); LC/MS (Table 2, Method d) R_(t)=2.04 min; MSm/z: 241 (M+H)⁺.

Example #241-(1-Benzylpiperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

Step A:(1-Benzylpiperidin-4-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol

n-BuLi (1.6 M in hexanes, 5.17 mL, 8.28 mmol) was added dropwise to asolution of5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.0 g,6.9 mmol, Adesis) in THF (120 mL) at about −78° C., keeping the internaltemperature of the reaction below about −70° C. during the addition.After stirring for about 40 min, 1-benzylpiperidine-4-carbaldehyde (2.1g, 10.3 mmol) was added dropwise and the resulting mixture was stirredat about −75° C. for about 1 h. The reaction was quenched by thedropwise addition of saturated aqueous ammonium chloride (60 mL). Themixture was concentrated under reduced pressure and the remainingaqueous portion was extracted with EtOAc (125 mL). The organic layer waswashed with brine (80 mL), dried over anhydrous MgSO₄ and concentratedunder reduced pressure to afford crude(1-benzylpiperidin-4-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-4-yl)methanol(3.53 g, quantitative) as a yellow oil: LC/MS (Table 2, Method n)R_(t)=1.82 min; MS m/z: 512 and 514 (M+H)⁺. The crude material was useddirectly in the next step without further purification.

Step B:(1-Benzylpiperidin-4-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone

Dess-Martin periodinane (8.78 g, 20.7 mmol) was added to a solution of(1-benzylpiperidin-4-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol(3.53 g, 6.9 mmol) in DCM (120 mL) at about 0° C., then stirred forabout 16 h while the reaction warmed to ambient temperature. The solventwas removed in vacuo and the residue partitioned between saturatedaqueous sodium bicarbonate (150 mL) and EtOAc (200 mL). The organicphase was washed with brine (120 mL), dried over anhydrous MgSO₄,filtered and concentrated under reduced pressure. Purification by silicagel chromatography, eluting first with heptanes (1 L) and then with 1:7EtOAc:heptanes (1 L) afforded(1-benzylpiperidin-4-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanoneas a white solid (1.85 g, 53% combined yield for Example #24 step A andstep B): LC/MS (Table 2, Method n) R_(t)=2.81 min; MS m/z: 510 and 512(M+H)⁺

Step C:4-((1-Benzylpiperidin-4-yl)(hydrazono)methyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine

The mixture of(1-benzylpiperidin-4-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone(1.85 g, 3.63 mmol), anhydrous hydrazine (0.341 mL, 10.9 mmol) and AcOH(0.21 mL, 3.63 mmol) was heated at reflux over 3 Å molecular sieves in aDean-Stark trap for about 48 h. The reaction mixture was cooled toambient temperatures, the solvent was removed under reduced pressure andthe residue partitioned between saturated NaHCO₃ (100 mL) and EtOAc (100mL). The organic layer was separated, washed with brine (100 mL), driedin vacuo over anhydrous MgSO₄ and concentrated. The residue wassuspended in Et₂O (15 mL) and the resulting precipitate was collected byfiltration and dried in vacuo to yield4-((1-benzylpiperidin-4-yl)(hydrazono)methyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine(0.85 g, 64%) as an off-white solid: LC/MS (Table 2, Method n)R_(t)=1.48 min; MS m/z: 368 and 370 (M+H)⁺.

Step D:1-(1-Benzylpiperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

A mixture of4-((1-benzylpiperidin-4-yl)(hydrazono)methyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine(0.85 g, 2.44 mmol), sodium tert-butoxide (0.565 g, 5.87 mmol),palladium acetate (0.0055 g, 0.024 mmol) and(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (0.0136 g, 0.0244 mmol) was heated in NMP (10 mL) at about160° C. in a CEM Discover microwave for about 30 min. The NMP wasremoved under reduced pressure and the residue was partitioned betweensaturated aqueous NaHCO₃ (50 mL) and EtOAc (50 mL). The organic phasewas separated, washed with brine (55 mL), dried over anhydrous MgSO₄ andconcentrated under reduced pressure. The residue was suspended in MeCN(10 mL) and the precipitate was collected by filtration and dried invacuo to yield1-(1-benzylpiperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridineas a tan solid (0.33 g, 40%): LC/MS (Table 2, Method n) R_(t)=1.42 min;MS m/z: 332 (M+H)⁺.

Example #251-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

Step A:1-(Piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

Ammonium formate (0.50 g, 7.9 mmol) and Pearlman's catalyst (0.56 g,0.79 mmol) were added to a solution of1-(1-benzylpiperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.26 g, 0.791 mmol, Example #24) in MeOH (20 mL). The reaction washeated at about 65° C. for about 1 h then filtered through Celite® andconcentrated under reduced pressure. The filtrate was concentrated toafford1-(piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.161 g, 84%): LC/MS (Table 2, Method a) R_(t)=1.18 min; MS m/z: 242(M+H), 240 (M−H)⁻. The crude product was used directly in subsequentsteps without further purification.

Step B:1-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

To a solution of1-(piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.023 g, 0.095 mmol) in pyridine (0.5 mL) was addedcyclopropanesulfonyl chloride (0.015 g, 0.105 mmol). The reaction wasstirred at about 25° C. for about 1 h. MeOH (0.5 mL) was added to quenchthe reaction and the crude reaction mixture was purified by RP-HPLC(Table 2, Method p) to afford1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridineas a solid (0.004 g, 6.5%): LC/MS (Table 2, Method a) R_(t)=1.74 min; MSm/z: 346 (M+H)⁺, 344 (M−H)⁻.

Example #261-(1-(Cyclopropylsulfonyl)piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

Step A:(1-Benzylpiperidin-3-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol

A solution of n-BuLi (1.6 N in heptane, 8.62 mL, 13.8 mmol) was addeddropwise to a solution of5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.00 g,11.5 mmol, Adesis) in THF (135 mL) at about −78° C., keeping thetemperature below about −70° C. After stirring for about 40 min, asolution of 1-benzylpiperidine-3-carbaldehyde (4.21 g, 20.7 mmol) in THF(15 mL) was added dropwise and the resulting mixture was stirred atabout −75° C. for about 2 h. The reaction was quenched by dropwiseaddition of saturated aqueous NH₄Cl (100 mL) and the THF was removedunder reduced pressure. The aqueous phase was extracted into EtOAc (250mL), washed with brine (200 mL), and concentrated to yield crude(1-benzylpiperidin-3-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol(5.88 g, quantitative) as a yellow oil that was used directly in thenext step without further purification: LC/MS (Table 2, Method a)R_(t)=1.78 min; MS m/z: 512 and 514 (M+H)⁺

Step B:(1-Benzylpiperidin-3-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone

Dess-Martin periodinane (14.63 g, 34.5 mmol) was added to a solution of(1-benzylpiperidin-3-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol(5.89 g, 11.5 mmol) in DCM (120 mL) at about 0° C. and the resultingmixture was stirred for about 16 h while warming to ambient temperature.The solvent was removed under reduced pressure and the residuepartitioned between saturated aqueous NaHCO₃ (150 mL) and EtOAc (200mL). The organic phase was washed with brine (120 mL) and concentratedunder reduced pressure. Purification by silica gel chromatographyeluting first with heptane (IL) and then with 1:7 EtOAc:heptane (1 L)yielded(1-benzylpiperidin-3-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone(1.45 g, 25%) as a yellow oil: LC/MS (Table 2, Method a) R_(t)=3.24 min;MS m/z: 511 (M+H)⁺

Step C:4-((1-Benzylpiperidin-3-yl)(hydrazono)methyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine

A mixture of(1-benzylpiperidin-3-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone(1.45 g, 2.84 mmol), anhydrous hydrazine (0.273 g, 8.53 mmol) and AcOH(0.163 mL, 2.84 mmol) was heated in EtOH (35 mL) at reflux for about 16h. The reaction mixture was cooled to room temperature, the solvent wasremoved under reduced pressure and the residue partitioned betweensaturated aqueous NaHCO₃ (50 mL) and EtOAc (60 mL). The organic phasewas washed with brine (40 mL) and concentrated to yield4-((1-benzylpiperidin-3-yl)(hydrazono)methyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine(1.04 g, quantitative) as a brown amorphous solid that was used directlyin the next step without further purification: LC/MS (Table 2, Method a)R_(t)=1.57 min; MS m/z: 368 (M+H)⁺.

Step D:1-(1-Benzylpiperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

A mixture of4-((1-benzylpiperidin-3-yl)(hydrazono)methyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine(1.04 g, 2.84 mmol), sodium tert-butoxide (0.652 g, 6.78 mmol),palladium acetate (0.0064 g, 0.028 mmol) and(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine (0.016 g, 0.028 mmol) in NMP (10 mL) was heated in themicrowave at about 160° C. for about 30 min. Additional palladiumacetate (0.0064 g, 0.028 mmol) and(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine (0.016 g, 0.028 mmol) were added and the mixture was heated ina microwave at about 160° C. for about 15 min. Additional palladiumacetate (0.003 g, 0.014 mmol) and(R)-1-[(−2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine (0.008 g, 0.014 mmol) were added and the mixture was againheated at about 160° C. for about 8 min. The solvent was removed underreduced pressure and the residue was partitioned between water (25 mL)and EtOAc (25 mL). The organic phase was washed with brine (20 mL),dried over anhydrous MgSO₄, decolorized with charcoal and filtered. Thesolvent was removed under reduced pressure and the residue purified bysilica gel chromatography, eluting first with DCM (1 L), a mixture of98:1:1 DCM:TEA:MeOH (1 L) and then with a mixture of 97:1:2 DCM:TEA:MeOH(1 L) to yield1-(1-benzylpiperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.18 g, 0.54 mmol, 19%) as a brown solid: LC/MS (Table 2, Method a)R_(t)=1.36 min; MS m/z: 332 (M+H)⁺.

Step E:1-(Piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

A mixture of1-(1-benzylpiperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.18 g, 0.54 mmol), Pearlman's catalyst (0.05 g, 0.36 mmol) andammonium formate (0.684 g, 10.8 mmol) was heated in EtOH (20 mL) atreflux for about 1 h. The catalyst was removed by filtration through aCelite® pad and the filtrate concentrated in vacuo to yield1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.13 g, 0.543 mmol, quantitative) as a yellow amorphous solid that wasused directly in the next step without further purification: LC/MS(Table 2, Method a) R_(t)=1.31 min; MS m/z: 242 (M+H)⁺.

Step F:1-(1-(Cyclopropylsulfonyl)piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

Cyclopropanesulfonyl chloride (0.076, 0.54 mmol) was added to a solutionof 1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.13 g, 0.54 mmol) in pyridine (5 mL), and the mixture was stirred atroom temperature for about 4 h. The solvent was removed in vacuo and theresidue purified by RP-HPLC (Table 2, Method q) to yield1-(1-(cyclopropylsulfonyl)piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.019 g, 0.055 mmol, 10%) as a white solid: LC/MS (Table 2, Method n)R_(t) 1.75 min; m/z: 346 (M+H)⁺.

Example #271-Cyclohexyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine

A solution containing 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(0.100 g, 0.554 mmol, Adesis), cyclohexylhydrazine hydrochloride (0.125g, 0.831 mmol) and DIEA (0.19 mL, 1.1 mmol) in t-BuOH (5 mL) was stirredat ambient temperature for about 1 h, then heated at about 70° C. forabout 1 h, followed by heating in a Biotage microwave at about 200° C.for about 1 h. The insoluble residue was removed by filtration and thefiltrate was subjected to purification by preparative RP-HPLC (Table 2,Method p) to yield1-cyclohexyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.045 g,0.187 mmol, 34%) as an off-white solid: LC/MS (Table 2, Method d,) R_(t)2.13 min; m/z: 241 (M+H)⁺, 239 (M−H)⁻.

Example #28 1-Cyclohexyl-6H-isoxazolo[4,5-d]pyrrolo[2,3-b]pyridine

Step A: (5-Chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanoneoxime

A mixture of(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone (0.35 g,1.33 mmol; Example #23, Step B), hydroxylamine hydrochloride (0.46 g,6.7 mmol), N,N-diisopropylethylamine (1.6 mL, 9.32 mmol) and AcOH (0.2mL, 3.5 mmol) in n-butanol (20 mL) was heated at about 120° C. for about18 h. Additional hydroxylamine hydrochloride (0.185 g, 2.66 mmol),N,N-diisopropylethylamine (0.70 mL, 4.0 mmol), and AcOH (0.15 mL, 2.7mmol) were added to the mixture and the reaction was heated at about120° C. for about 18 h. Additional amounts of hydroxylaminehydrochloride (0.185 g, 2.66 mmol), DIEA (0.70 mL, 4.0 mmol), and AcOH(0.15 mL, 2.7 mmol) were added to the mixture and the reaction washeated at about 130° C. for about 3 days. The reaction was cooled toambient temperature and concentrated under reduced pressure. The residuewas diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO₃(3×40 mL) and brine (20 mL), dried over anhydrous MgSO₄, filtered andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography (0-70% EtOAc in heptane gradient as the eluentto provide (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanoneoxime as an off white solid (0.193 g, 52%): LC/MS (Table 2, Method a)R_(t)=2.22 min; m/z: 276 and 278 (M−H)⁻.

Step B: 1-Cyclohexyl-6H-isoxazolo[4,5-d]pyrrolo[2,3-b]pyridine

A mixture of(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone oxime(0.19 g, 0.70 mmol) and potassium tert-butoxide (0.16 g, 1.4 mmol) inDMSO (6 mL) was heated in a Biotage microwave at about 125° C. for about30 min. The solvent was removed under reduced pressure and the crudeproduct was purified by silica gel chromatography (0-30% EtOAc inheptane gradient as the eluent to afford1-cyclohexyl-6H-isoxazolo[4,5-d]pyrrolo[2,3-b]pyridine as a white solid(0.076 g, 46%): LC/MS (Table 2, Method d) R_(t)=2.50 min; m/z: 242(M+H)⁺.

Example #291-Cyclohexyl-3-methyl-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

Step A:5-Chloro-4-(cyclohexyl(2-methylhydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine

A mixture of(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone (0.383 g,1.46 mmol; Example #23, Step B), methylhydrazine (0.24 mL, 4.56 mmol),and AcOH (0.084 mL, 1.47 mmol) in n-butanol (10 mL) was heated at about135° C. for about 18 h. During this time, water was distilled from thereaction mixture via the use of a Dean-Stark trap. Additionalmethylhydrazine (0.24 mL, 4.6 mmol) and AcOH (0.084 mL, 1.5 mmol) wereadded and the reaction mixture was heated at reflux for about 2 days.The reaction was cooled to ambient temperature and concentrated underreduced pressure. The crude product was diluted with EtOAc (50 mL),washed with saturated aqueous NaHCO₃ (30 mL) and brine (30 mL), driedover anhydrous MgSO₄, filtered and concentrated under reduced pressure.The crude product was purified by silica gel chromatography (0-35% EtOAcin heptane gradient as the eluent to provide5-chloro-4-(cyclohexyl(2-methylhydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine(0.261 g, 62%): LC/MS (Table 2, Method d) R_(t)=2.53 min; m/z: 291 and293 (M+H)⁺.

Step B:1-Cyclohexyl-3-methyl-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

A mixture of5-chloro-4-(cyclohexyl(2-methylhydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine(0.241 g, 0.829 mmol), sodium tert-butoxide (0.191 g, 1.99 mmol),palladium acetate (0.001 g, 0.0083 mmol) and(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (0.0046 g, 0.0083 mmol), was heated in NMP (3 mL) at about160° C. for about 15 min in a Biotage microwave. Additional palladiumacetate (0.001 g, 0.0083 mmol) and(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (0.0046 g, 0.0083 mmol) was added and the reaction mixture washeated at about 160° C. for about 30 min. The insoluble residue wasremoved by filtration through a Celite® pad and to the filtrate waspurified by preparative RP-HPLC (Table 2, Method r) to provide1-cyclohexyl-3-methyl-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridineas a white solid (0.121 g, 58%): LC/MS (Table 2, Method d) R_(t)=2.29min; m/z: 255 (M+H)⁺.

Example #301-Cyclobutyl-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

Step A: Cyclobutylmagnesium bromide

Magnesium (4.63 g, 191 mmol) was heated at about 120° C. in a dry flaskunder a nitrogen atmosphere for about 1 min. The flask was cooled toabout 60° C., THF (56 mL), 1,2-dibromoethane (0.055 mL, 0.64 mmol) andbromocyclobutane (6 mL, 64 mmol) were added. The reaction mixture wasstirred at about 60° C. for about 5 h then used directly in the nextstep.

Step B: (5-Chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclobutyl)methanol

The solution of cyclobutylmagnesium bromide (0.28 M in THF, 56 mL, 63mmol) was added to a solution of5-chloro-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (0.908 g, 5.03 mmol,Adesis) in THF (30 mL) at about 0° C. The reaction mixture was stirredand allowed to warm to ambient temperature and the reaction mixture wasstirred for about 16 h. Water (10 mL) was added and the volatiles wereremoved under reduced pressure. The product was extracted into DCM (3×20mL) and the combined organic phases were dried over anhydrous MgSO₄,filtered, the solvent was removed under reduced pressure and the crudematerial was purified by column chromatography over silica gel using a10 to 45% gradient of EtOAc in heptane as the eluent to provide(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclobutyl)methanol as an offwhite solid (0.42 g, 32%); LC/MS (Table 2, Method a) R_(t)=2.02 min;m/z: 237 and 239 (M+H)⁺.

Step C: (5-Chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclobutyl)methanone

Dess-Martin periodinane (1.6 g, 3.8 mmol) was added to a suspension of(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclobutyl)methanol (0.3 g, 1.2mmol) in DCM (7 mL) at about 0° C. The reaction mixture was stirred atambient temperature for about 4 h then quenched by the addition of withsaturated aqueous Na₂SO₃ (125 mL). The product was extracted into DCM(3×20 mL) and the combined organic extracts were washed with aqueousNaOH (2 N, 20 mL). The organic phase was dried over anhydrous MgSO₄ andthe solvent was removed under reduced pressure to provide(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclobutyl)methanone as anoff-white solid (0.2 g, 67%) that was used directly in the next stepwithout further purification: LC/MS (Table 2, Method a) R_(t)=2.27 min;m/z: 235 and 237 (M+H)⁺.

Step D:5-Chloro-4-(cyclobutyl(hydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine

A mixture of(5-chloro-11H-pyrrolo[2,3-b]pyridin-4-yl)(cyclobutyl)methanone (0.2 g,0.85 mmol), anhydrous hydrazine (0.13 mL, 4.26 mmol) and AcOH (0.008 mL,0.142 mmol) in ethanol (10 mL) was heated at reflux for about 20 h.During this time, water was distilled from the reaction mixture via theuse of a Dean-Stark trap. The volatiles were removed under reducedpressure and the residue was partitioned between water (10 mL) and EtOAc(20 mL). The organic phase was dried over anhydrous MgSO₄, filtered, andthe solvent evaporated under reduced pressure. The crude material waspurified by chromatography over silica gel using a 10 to 50% gradient ofEtOAc in heptane as the eluent to provide5-chloro-4-(cyclobutyl(hydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine as anoff-white solid (0.10 g, 49%): LC/MS (Table 2, Method o) R_(t)=2.22 min;m/z: 249 and 251 (M+H)⁺.

Step E: 1-Cyclobutyl-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

A mixture of5-chloro-4-(cyclobutyl(hydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine(0.052 g, 0.21 mmol), sodium tert-butoxide (0.048 g, 0.50 mmol),palladium acetate (0.0005 g, 0.0025 mmol) and(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (0.0015 g, 0.0025 mmol) was heated in N-methyl-2-pyrrolidinone(2 mL) at about 160° C. in a CEM Discover microwave for about 30 min.The insoluble residue was removed by filtration and the filtrate wassubjected to purification by preparative RP-HPLC (Table 2, Method h) toyield 1-cyclobutyl-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine as awhite solid (0.002 g, 4%): LC/MS (Table 2, Method d) R_(t)=1.78 min;m/z: 213 (M+H)⁺.

Example #311-(Tetrahydro-2H-pyran-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

5-Chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.0 g,2.3 mmol, Adesis) and tetrahydro-2H-pyran-4-carbaldehyde (0.47 g, 4.1mmol, Pharmacore) in THF (46 mL) were reacted according to theconditions specified in Example #24. The crude material was purified byRP-HPLC (Table 2, Method s) to give1-(tetrahydro-2H-pyran-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridineas a tan solid (0.027 g, 4% over 4 steps): LC/MS (Table 2, Method a)R_(t)=1.51 min; m/z: 243 (M+H)⁺.

Example #321-(Tetrahydro-2H-pyran-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

5-Chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.0 g,2.3 mmol, Adesis) and tetrahydro-2H-pyran-3-carbaldehyde (0.47 g, 4.1mmol, JW Pharmlab) in THF (46 mL) were reacted according to theconditions specified in Example #24. The crude material was purified byRP-HPLC (Table 2, Method s) to give1-(tetrahydro-2H-pyran-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.0021 g, 0.4% over 4 steps): LC/MS (Table 2, Method a) R_(t)=1.53 min;m/z: 243 (M+H)⁺.

Example #336-((1S,3S)-3-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrileand6-((1S,3R)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile

A mixture of(1S)-3-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine(0.20 g, 0.83 mmol, Preparation #30), 6-chloronicotinonitrile (0.12 g,0.83 mmol), DIEA (0.22 mL, 1.2 mmol), and EtOH (3 mL) were heated forabout 1 h at about 120° C. in a microwave (250 psi maximum pressure, 1min ramp, 300 max watts). The reaction mixture was concentrated in vacuoand purified by RP-HPLC (Table 2, Method s) to give6-((1S,3S)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile(0.014 g, 5%): LC/MS (Table 2, Method a) R_(t)=1.75 min; m/z: 344 (M+H)⁺and6-((1S,3R)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile(0.020 g, 7%): LC/MS (Table 2, Method a) R_(t)=1.81 min; m/z: 344(M+H)⁺.

Example #341-(1-(5-(Trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

A mixture of1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.16 g, 0.65 mmol, Example #26, Step E) and2-chloro-5-(trifluoromethyl)pyridine (0.031 g, 0.17 mmol) with DIEA(0.09 mL, 0.51 mmol) in EtOH (2 mL) was heated at about 130° C. forabout 1 h in a microwave reactor (250 psi maximum pressure, 1 min ramp,300 max watts). The crude material was purified by silica gelchromatography eluting with a 5-100% EtOAc in heptane gradient to give1-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.016 g, 24%): LC/MS (Table 2, Method a) R_(t)=2.32 min; m/z: 387(M+H)⁺.

Example #356-(3-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)pyridazine-3-carbonitrile

A mixture of1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.16 g, 0.65 mmol, Example #26, Step E) and6-chloropyridazine-3-carbonitrile (0.090 g, 0.65 mmol) with DIEA (0.37mL, 2.12 mmol) in EtOH (3 mL) was heated at about 120° C. for about 15min in a microwave reactor (250 psi maximum pressure, 1 min ramp, 300max watts). The crude material was purified by RP-HPLC (Table 2, Methodh) to give6-(3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)pyridazine-3-carbonitrile(0.016 g, 24%): LC/MS (Table 2, Method a) R_(t)=1.76 min; m/z: 345(M+H)⁺.

Example #366-(3-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)nicotinonitrile

A mixture of1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.16 g, 0.65 mmol, Example #26, Step E) and 6-chloronicotinonitrile(0.090 g, 0.65 mmol) with DIEA (0.37 mL, 2.12 mmol) in EtOH (3 mL) washeated at about 120° C. for about 15 min in a microwave reactor. Thecrude material was purified by RP-HPLC (Table 2, Method h) to give6-(3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)nicotinonitrile(0.012 g, 6%): LC/MS (Table 2, Method a) R_(t)=1.96 min; m/z: 344(M+H)⁺.

Example #371-(Piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine

1-(Piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine wasprepared in a manner analogous to Example #26, Steps A-E by substituting1-benzylpiperidine-3-carbaldehyde with1-benzylpiperidine-4-carbaldehyde. Purification by RP-HPLC (Table 2,Method t) gave1-(piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine(0.038 g, 3% over 5 steps): LC/MS (Table 2, Method a) R_(t)=0.84 min;m/z: 242 (M+H)⁺.

Example #386-((1S,3S)-3-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile and 6-((1S,3R)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile

(3R)-3-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine(0.12 g, 0.48 mmol, Preparation #29), 6-chloronicotinonitrile (0.069 g,0.48 mmol), and DIEA (0.13 mL, 0.75 mmol) were heated in EtOH (3.0 mL)at about 80° C. for about 10 h. The solvent was removed under reducedpressure and the crude material was purified by RP-HPLC (Table 2, Methodh) to give6-((1R,3R)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile(0.007, 4%): LC/MS (Table 2, Method a) R_(t)=1.86 min; m/z: 344 (M+H)⁺and6-((1R,3S)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile(0.009 g, 5%): LC/MS (Table 2, Method a) R_(t)=1.89 min; m/z: 344(M+H)⁺.

Example #39N-((1R,3R)-3-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentyl)cyclopropanesulfonamideandN-((1R,3S)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentyl)cyclopropanesulfonamide

(3R)-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine(0.12 g, 0.48 mmol, Preparation #29), cyclopropanesulfonyl chloride(0.070 g, 0.48 mmol), DIEA (0.11 mL, 0.60 mmol), and DMF (6.0 mL) werestirred at room temperature for about 2.5 h. The solvent was removedunder reduced pressure and the crude material was purified by RP-HPLC(Table 2, Method q) to giveN-((1R,3R)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentyl)cyclopropanesulfonamide(0.008 g, 5%): LC/MS (Table 2, Method a) R_(t)=1.58 min; m/z: 346 (M+H)⁺andN-((1R,3S)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentyl)cyclopropanesulfonamide(0.017 g, 10%): LC/MS (Table 2, Method a) R_(t)=1.71 min; m/z: 346(M+H)⁺.

Example #402-Cyano-N-((1R,3S)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentyl)acetamide

(3R)-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine(0.12 g, 0.48 mmol, Preparation #29) and 2-cyanoacetic acid (0.042 g,0.48 mmol), were combined in DMF (6.0 mL) with EDC (0.12 g, 0.65 mmol)and HOBt (0.076 g, 0.48 mmol). The mixture was stirred for about 3 h atroom temperature. Perfluorophenyl 2-cyanoacetate (0.62 g, 2.5 mmol,Preparation #6) was added and the reaction mixture was stirred for about48 h at room temperature. The solvent was removed under reduced pressureand the crude material was purified by RP-HPLC (Table 2, Method q) togive2-cyano-N-((1R,3S)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentyl)acetamide(0.014 g, 9%): LC/MS (Table 2, Method a) R_(t)=1.52 min; m/z: 307(M−H)⁻.

Example #411-Methyl-7-(3-(methylsulfonyl)phenyl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine

Step A: 1-Methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine

4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1.37 g, 7.59 mmol,Adesis) and methylhydrazine (0.599 mL, 11.4 mmol) in n-BuOH (7 mL) wereheated to about 95° C. After about 15 min, concentrated HCl (0.500 mL,16.4 mmol) was added and the reaction mixture was heated to about 120°C. After about 4 h, water (10 mL) was added and the mixture wasextracted with EtOAc (20 mL). The organic layer was separated and theaqueous layer was basified with saturated aqueous NaHCO₃ to about pH 8and extracted with EtOAc (2×20 mL). The combined organic layers weredried over anhydrous MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography (40 gcolumn) eluting with a gradient of 5-60% EtOAc in heptane to give1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.960 g,74%): LC/MS (Table 2, Method d) R_(t)=1.40 min; MS m/z: 173 (M+H)⁺.

Step B:1-Methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine

To a solution of NaH (60% dispersion in mineral oil, 0.209 g, 5.23 mmol)in DMF (10 mL) at about 0° C. was added a solution of1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.60 g, 3.5mmol) in DMF (5 mL). The cooling bath was removed and after about 20min, p-toluenesulfonyl chloride (0.996 g, 5.23 mmol) was added. Afterabout 2 h at room temperature, water was added (15 mL) and the mixturewas extracted with EtOAc (3×20 mL). The organic layers were combined,dried over anhydrous MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith a gradient of 5-45% EtOAc in heptane to give1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.50g, 44%): LC/MS (Table 2, Method d) R_(t)=2.20 min; MS m/z: 327 (M+H)⁺.

Step C:7-Iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine

Diisopropylamine (0.20 mL, 1.5 mmol) in THF (1.5 mL) was cooled to about−74° C. A solution of n-BuLi (1.6 M solution in cyclohexane, 1.03 mL,1.65 mmol) was added drop-wise over about 15 min. After about 20 min,the solution was added to1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.250g, 0.766 mmol) in THF (10 mL) at about −74° C. over about 10 min. Afterabout 1 h at about −74° C., a solution of iodine (0.226 g, 0.889 mmol)in THF (5 mL) was added over about 5 min. After about 2 h at about −74°C., water (20 mL) was added and the reaction mixture was extracted withEtOAc (3×20 mL). The organic layers were combined, dried over anhydrousMgSO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography eluting with a gradient of5-40% EtOAc in heptane to give7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine(0.27 g, 78%): LC/MS (Table 2, Method d) R_(t)=2.34 min; MS m/z: 453(M+H)⁺.

Step D:1-Methyl-7-(3-(methylsulfonyl)phenyl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine

A mixture of7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine(0.134 g, 0.296 mmol), 3-(methylsulfonyl)phenylboronic acid (0.711 g,0.356 mmol, Combi-Blocks), Pd(PPh₃)₄ (0.24 g, 0.021 mmol, Strem), Na₂CO₃(0.790 g, 0.741 mmol) in 1,4-dioxane:water (3:1, mL) was heated to about90° C. for about 5 h. The reaction mixture was filtered through a plugof Celite®. The filtrate was washed with water (10 mL), dried overanhydrous MgSO₄, filtered, and concentrated under reduced pressure togive1-methyl-7-(3-(methylsulfonyl)phenyl)-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine(0.180 g, 0.375 mmol) that was dissolved in MeOH (3 mL) and treated withaqueous NaOH (5 N, 0.75 mL, 3.8 mmol) The reaction vessel was sealed andheated in a CEM microwave at about 120° C. for about 20 min (250 psimaximum pressure, 2 min ramp time, 300 max watts). The reaction mixturewas filtered and washed with MeOH (3 mL). The filtrate was concentratedin vacuo, and purified by silica gel chromatography eluting with agradient of 0-10% MeOH in DCM to give1-methyl-7-(3-(methylsulfonyl)phenyl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine(0.65 g, 53%): LC/MS (Table 2, Method d) R_(t)=1.23 min; MS m/z: 327(M+H)⁺.

Example #427-(5-Methoxy-1-methyl-1H-indol-3-yl)-1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine

A flask was charged with7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine(0.200 g, 0.442 mmol, Example #41, Step C),5-methoxy-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(0.140 g, 0.486 mmol, Preparation #31), Pd(PPh₃)₄ (0.036 g, 0.031 mmol,Strem) and Na₂CO₃ (0.117 g, 1.11 mmol) in 1,4-dioxane:water (3:1, 10mL). The reaction mixture was heated at about 85-90° C. for about 5 h.The reaction mixture was filtered, concentrated to dryness under reducedpressure to give a crude solid that was added to a microwave reactionvessel. MeOH (3 mL) and aqueous NaOH (5 N, 0.412 mL, 2.06 mmol) wereadded and the vessel was sealed and heated to about 120° C. in amicrowave for about 20 min (250 psi maximum pressure, 2 min ramp time,300 max watts). The reaction mixture was filtered and washed with MeOH.The filtrate was concentrated in vacuo, and purified by silica gelchromatography eluting with a gradient of 5-68% EtOAc in heptane to give7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine(0.015 g, 22% over 2 steps): LC/MS (Table 2, Method d) R_(t)=1.30 min;MS m/z: 332 (M+H)⁺.

Example #431-Methyl-7-(1-methyl-1H-pyrazol-4-yl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine

A flask was charged with7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine(0.134 g, 0.296 mmol, Example #41, Step C),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.074 g, 0.36 mmol), (PPh₃)₄ (0.024 g, 0.021 mmol, Strem) and Na₂CO₃(0.079 g, 0.74 mmol) in 1,4-dioxane:water (3:1, 10 mL) The reaction washeated at about 80° C. for about 12 h. The mixture was filtered and thefiltrate was concentrated under reduced pressure to give a solid thatwas added to a 5 mL microwave reaction vial. MeOH (3 mL) and aqueousNaOH (5 N, 0.77 ml, 3.8 mmol) were added and the reaction vessel wassealed and heated to about 120° C. in a microwave for about 20 min (250psi maximum pressure, 2 min ramp time, 300 max watts). The reactionmixture was filtered and washed with MeOH. The filtrate wasconcentrated, redissolved in MeOH/DCM, and purified by silica gelchromatography (12 g column) eluting with a gradient of 0-5% MeOH inDCM. The product-containing fractions were combined and concentrated togive1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine(0.038 g, 39% over 2 steps): LC/MS (Table 2, Method d) R_(t)=1.13 min;MS m/z: 253 (M+H)⁺.

Example #447-(5-Methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

Step A: tert-Butyl2-(6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate

A round bottom flask was charged withtris(dibenzylidineacetone)dipalladium(0) (0.066 g, 0.072 mmol) anddi-tert-butyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (0.061 g,0.14 mmol) in 1,4-dioxane (10 mL) to give a black solution which wasdegassed via vacuum/nitrogen purge (3 times). The mixture was heated toabout 80° C. for about 10 min. To the reaction mixture were added2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine(0.35 g, 0.72 mmol, Example #20, Step D) and tert-butylhydrazinecarboxylate (0.142 g, 1.08 mmol), followed by sodiumtert-butoxide (0.104 g, 1.08 mmol). The mixture was heated at about 80°C. for about 20 min. The reaction mixture was cooled and filteredthrough Celite®. The filter pad was further rinsed with EtOAc (40 mL).The filtrate was concentrated under reduced pressure and purified bysilica gel chromatography eluting with a gradient of 0-100% EtOAc inheptane to give tert-butyl2-(6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(0.272 g, 70%): LC/MS (Table 1, Method d) R_(t)=1.78 min; MS m/z: 539(M+H)⁺.

Step B:2-Hydrazinyl-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

To a round bottom flask were added tert-butyl2-(6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate(0.272 g, 0.505 mmol) and 1,4-dioxane (5 mL). To the mixture was addedHCl (4 N in 1,4-dioxane, 1.26 ml, 5.05 mmol) and the reaction mixturewas heated to about 60° C. for about 1 h. The reaction mixture wascooled to room temperature and was diluted with EtOAc (50 mL). Thesolution was washed with saturated aqueous NaHCO₃ (50 mL), dried overanhydrous MgSO₄, filtered, and concentrated under reduced pressure togive2-hydrazinyl-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine(0.19 g, 84%): LC/MS (Table 1, Method d) R_(t)=1.55 min; MS m/z: 439(M+H)⁺.

Step C:7-(5-Methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a round bottom flask were added2-hydrazinyl-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine(0.181 g, 0.413 mmol), DCM (5 mL) and acetaldehyde (10.0 M in DCM, 0.206mL, 2.06 mmol). The reaction mixture was stirred at room temperature forabout 1 h. The reaction mixture was concentrated under reduced pressurefollowed by the addition of DMF (8 mL) and copper(II) chloride (0.107 g,0.796 mmol). The reaction mixture was heated to about 90° C. for about15 min. The reaction mixture was cooled to room temperature and 10%aqueous ammonia (4.5 mL) and EtOAc (6 mL) were added. The reactionmixture was heated to about 40° C. for about 30 min. The reactionmixture was cooled to ambient temperature and extracted with EtOAc (50mL). The organic layer was washed with water (50 mL), dried overanhydrous MgSO₄, filtered, and concentrated under reduced pressure. Thematerial was purified by silica gel chromatography eluting with agradient of 0-100% EtOAc in heptane to give7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2, 4]triazolo[4,3-a]pyrazine (0.040 g, 21%): LC/MS (Table 1, Method d)R_(t)=1.67 min; MS m/z: 463 (M+H)⁺.

Step D:7-(5-Methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a round bottom flask was added7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.040 g, 0.086 mmol), DMF (0.865 mL), ethylenediamine (0.088 mL, 2.6mmol) and TBAF (1.0 M in THF, 0.346 mL, 0.173 mmol). The reactionmixture was heated to about 85° C. for about 4 h. To the reactionmixture was added ethylenediamine (0.088 mL, 2.6 mmol) and TBAF (1.0 Min THF, 0.346 mL, 0.173 mmol). The reaction mixture was heated at about85° C. for about 2 h. The reaction mixture cooled to room temperatureand diluted with water (50 mL). The mixture was extracted with EtOAc (50mL) and the organic layer was dried over anhydrous MgSO₄, filtered, andconcentrated under reduced pressure. The crude material was purified bypreparatory RP-HPLC (Table 2, Method u). The material was furtherpurified by silica gel chromatography eluting with a gradient of 0-10%MeOH in DCM to give7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine(0.0024 g, 8.4%). LC/MS (Table 1, Method a) R_(t)=1.84 min; MS m/z: 333(M+H)⁺.

What is claimed:
 1. A compound of formula (I)

pharmaceutically acceptable salts, stereoisomers and isomers thereofwherein T is N, U is N, X is CR³ and Y is N; or T is CR⁶, U is N, X isCR³ and Y is N; or T is N, U is CR⁴, X is CR³ and Y is N; or T is CR⁶, Uis CR⁴, X is CR³ and Y is N; or T is CR⁶, U is N, X is NR³ and Y is C;or T is O, U is N, X is CR³ and Y is C; or T is NR⁶, U is N, X is CR³and Y is C; or T is CR⁶, U is CR⁴, X is NR³ and Y is C; or T is S, U isN, X is CR³ and Y is C; R¹ and R² are each independently hydrogen,deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)(R^(b)), —C(O)R^(a), —C(OH)R^(a)R^(b),—N(R^(a))S(O)₂—R^(b), —S (O)₂N(R^(a))(R^(b)), —CF₃, —OCF₃, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, optionally substituted(C₃-C₁₀)cycloalkyl, optionally substituted (C₁-C₁₀)heteroaryl,optionally substituted (C₁-C₁₀) heterocyclyl, or optionally substituted(C₆-C₁₀)aryl; R⁵ is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen,—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN,—C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)(R^(b)), —C(O)R^(a),—C(OH)R^(a)R^(b), —N(R^(a))S(O)₂—R^(b), —S(O)₂N(R^(a))(R^(b)), —CF₃,—OCF₃, optionally substituted (C₁-C₆)alkyl, optionally substituted(C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl, optionallysubstituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₁-C₁₀)heteroaryl, optionally substituted (C₁-C₁₀) heterocyclyl, oroptionally substituted (C₆-C₁₀)aryl; wherein in a moiety containing—N(R^(a))(R^(b)), the nitrogen, R^(a) and R^(b) may form a ring suchthat —N(R^(a))(R^(b)) represents an optionally substituted(C₂-C₁₀)heterocyclyl or optionally substituted (C₁-C₁₀)heteroaryl linkedthrough a nitrogen; R³ is an optionally substituted bridged(C₅-C₁₂)cycloalkyl, optionally substituted bridged (C₂-C₁₀)heterocyclyl,optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₈)cycloalkenyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl, optionally substituted (C₂-C₁₀)heterocyclyl; or R³ is -A-D-E-G, wherein: A is a bond, —C(O)—,optionally substituted (C₁-C₆)alkylene, optionally substituted(C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene, optionallysubstituted (C₃-C ₁₂)cycloalkylene, optionally substituted(C₂-C₆)heterocyclylene, —C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—,—O—R^(e)—, —N(R^(a))—R^(e)—, —S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)—or —N(R^(a))C(O)N(R^(b))—R^(e)—; D is optionally substituted bridged(C₅-C₁₂)cycloalkylene, optionally substituted (C₃-C ₁₀)cycloalkylene,optionally substituted bridged (C₅-C ₁₀)cycloalkenylene, optionallysubstituted (C₃-C ₁₀)cycloalkenylene, optionally substituted(C₆-C₁₀)arylene, optionally substituted (C₁-C₁₀)heteroarylene,optionally substituted bridged (C₂-C ₁₀)heterocyclylene or an optionallysubstituted (C₂-C ₁₀)heterocyclylene; E is a bond, —R^(e)—,—R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—, —R^(e)—C(O)O—R^(e)—,—R^(e)—C(O)C(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))—C(O)C(O)—R^(e)—,—R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—, —R^(e)—S(O)—R^(e)—,—R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)—R^(e)—,—R^(e)C(O)N(R^(a))R^(e)—, —R^(e)—OC(O)N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)OR^(e)—, —R^(e)—OC(O)—R^(e),—R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—, or—R^(e)—S(O)₂N(R^(a))—R^(e)—; or E is

where in all cases, E is linked to either a carbon or a nitrogen atom inD; G is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN,—C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b),—OC(O)N(R^(a)), —N(R^(a))C(O)N(R^(b))₂, —C(O—R^(a))(R^(b))₂, —C(O)R^(a),—CF₃, —OCF₃, —N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)),—S(O)₂N(R^(a))C(O)R^(b), an optionally substituted —(C₁-C₆)alkyl, anoptionally substituted —(C₂-C₆)alkenyl, an optionally substituted—(C₂-C₆)alkynyl, an optionally substituted —(C₃-C₁₀)cycloalkyl, anoptionally substituted —(C₁-C₁₀)heteroaryl, an optionally substituted—(C₁-C₁₀) heterocyclyl, an optionally substituted —(C₆-C₁₀)aryl, anoptionally substituted —(C₁-C₆)alkyl-(C₃-C₁₀)cycloalkyl, an optionallysubstituted —(C₁-C₆)alkyl-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkyl-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkyl-(C₁-C₁₀)heterocyclyl; wherein in a moiety containing—N(R^(a))(R^(b)), the nitrogen, R^(a) and R^(b) may form a ring suchthat —N(R^(a))(R^(b)) represents an optionally substituted(C₂-C₁₀)heterocyclyl or an optionally substituted (C₁-C₁₀) heteroaryllinked through a nitrogen; R⁴ and R⁶ are each independently a hydrogen,halogen, deuterium, an optionally substituted bridged (C₅-C₁₂)cycloalkylgroup, optionally substituted bridged (C₂-C₁₀)heterocyclyl group,optionally substituted (C₁-C₈)alkyl, optionally substituted(C₃-C₁₀)cycloalkyl, optionally substituted (C₃-C₈)cycloalkenyl,optionally substituted (C₆-C₁₀)aryl, optionally substituted(C₁-C₁₀)heteroaryl, optionally substituted (C₂-C₁₀)heterocyclyl or-J-L-M-Q; wherein: J is a bond, —C(O)—, optionally substituted(C₁-C₆)alkylene, optionally substituted (C₂-C₆)alkenylene, optionallysubstituted (C₂-C₆)alkynylene, optionally substituted (C₃-C₁₂)cycloalkylene, optionally substituted (C₂-C₆)heterocyclylene,—C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—, —O—R^(e)—, —N(R^(a))—R^(e)—,—S—R^(e)—, —S(O)₂—R^(e)—, —S(O)R^(e)—, —C(O—R^(a))(R^(b))—R^(e)—,—S(O)₂N(R^(a))—R^(e)—, —N(R^(a))S(O)₂—R^(e)— or—N(R^(a))C(O)N(R^(b))—R^(e)—; L is an optionally substituted(C₁-C₈)alkylene, optionally substituted bridged (C₅-C₁₂)cycloalkylene,optionally substituted (C₃-C₁₀)cycloalkylene, optionally substitutedbridged (C₅-C₁₀)cycloalkenylene, optionally substituted(C₃-C₁₀)cycloalkenylene, optionally substituted (C₁-C₁₀)heteroarylene,optionally substituted bridged (C₂-C₁₀)heterocyclylene or an optionallysubstituted (C₂-C₁₀)heterocyclylene; M is a bond, —R^(e)—,—R^(e)—C(O)—R^(e)—, —R^(e)—C(O)C(O)—R^(e)—, —R^(e)—C(O)O—R^(e)—,—R^(e)—OC(O)—R^(e), —R^(e)—C(O)C(O)N(R^(a))—R^(e)—,—R^(e)—N(R^(a))—C(O)C(O)—R^(e)—, —R^(e)—O—R^(e)—, —R^(e)—S(O)₂—R^(e)—,—R^(e)—S(O)—R^(e)—, —R^(e)—S—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—N(R^(a))C(O)—R^(e)—, —R^(e)—C(O)N(R^(a))R^(e)—,—R^(e)—OC(O)N(R^(a))—R^(e)—, —R^(e)—N(R^(a))C(O)OR^(e)—,—R^(e)—N(R^(a))C(O)N(R^(b))—R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—, or—R^(e)—S(O)₂N(R^(a))—R^(e)—; or M is

where in all cases, M is linked to either a carbon or a nitrogen atom inL; Q is hydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN,—C(O)N(R^(a))(R^(b)), —N(R^(a))C(O)R^(b), —N(R^(a))C(O)OR^(b),—N(R^(a))C(O)N(R^(b))₂, —C(O—R^(a))(R^(b))₂, —C(O)R^(a), —CF₃, —OCF₃,—N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)), —S(O)₂N(R^(a))C(O)R^(b), anoptionally substituted (C₁-C₆)alkyl, an optionally substituted(C₂-C₆)alkenyl, an optionally substituted (C₂-C₆)alkynyl, an optionallysubstituted (C₃-C₁₀)cycloalkyl, an optionally substituted(C₁-C₁₀)heteroaryl, an optionally substituted (C₁-C₁₀) heterocyclyl, anoptionally substituted (C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkyl-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkyl-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkyl-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkyl-(C₁-C₁₀)heterocyclyl; wherein in a moiety containing—N(R^(a))(R^(b)), the nitrogen, R^(a) and R^(b) may form a ring suchthat —N(R^(a))(R^(b)) represents an optionally substituted(C₂-C₁₀)heterocyclyl or an optionally substituted (C₁-C₁₀) heteroaryllinked through a nitrogen; R^(a) and R^(b) are each independentlyhydrogen, deuterium, an optionally substituted (C₁-C₁₀)alkyl, anoptionally substituted (C₂-C₁₀)alkenyl, an optionally substituted(C₂-C₁₀)alkynyl, an optionally substituted(C₁-C₁₀)alkyl-O—(C₁-C₁₀)alkyl, an optionally substituted(C₃-C₁₀)cycloalkyl, an optionally substituted (C₆-C₁₀)aryl, anoptionally substituted (C₁-C₁₀)heteroaryl, an optionally substituted(C₁-C₁₀)heterocyclyl, an optionally substituted—(C₁-C₆)alkylene-(C₃-C₁₀)cycloalkyl, an optionally substituted—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heteroaryl, or an optionally substituted—(C₁-C₆)alkylene-(C₁-C₁₀)heterocyclyl; and R^(e) for each occurrence isindependently a bond, an optionally substituted (C₁-C₁₀)alkylene, anoptionally substituted (C₂-C₁₀)alkenylene, an optionally substituted(C₂-C₁₀)alkynylene, an optionally substituted—(C₁-C₁₀)alkylene-O—(C₁-C₁₀)alkylene group, an optionally substituted(C₃-C ₁₀)cycloalkylene, an optionally substituted (C₁-C₁₀)heteroarylene,or an optionally substituted (C₁-C₁₀)heterocyclylene; provided that whenthe compound is

R³ is defined as above and R⁶ is not linked to the pyrazole ring by anitrogen or oxygen atom; and provided that when the compound is

when R³ is H, CH₃ or —C(O)OH then R⁴ is not H, —C(O)OCH₂CH₃,—C(O)NH—optionally substituted phenyl, —NHC(O)-optionally substitutedphenyl or —S(O)₂-phenyl.
 2. The compound of claim 1 wherein T is N, U isN, X is CR³ and Y is N and forms a compound of Formula (Ia)


3. The compound of claim 1 wherein T is CR⁶, U is N, X is CR³ and Y is Nand forms a compound of Formula (Ib)


4. The compound of claim 1 wherein T is N, U is CR⁴, X is CR³ and Y is Nand forms a compound of Formula (Ic)


5. The compound of claim 1 wherein T is CR⁶, U is CR⁴, X is CR³ and Y isN and forms a compound of Formula (Id)


6. The compound of claim 1 wherein T is CR⁶, U is N, X is NR³ and Y is Cand forms a compound of Formula (Ie)


7. The compound of claim 1 wherein T is O, U is N, X is CR³ and Y is Cand forms a compound of Formula (If)


8. The compound of claim 1 wherein T is NR⁶, U is N, X is CR³ and Y is Cand forms a compound of Formula (Ig)


9. The compound of claim 1 wherein T is CR⁶, U is CR⁴, X is NR³ and Y isC and forms a compound of Formula (Ih)


10. The compound of claim 1 wherein T is S, U is N, X is CR³ and Y is Cand forms a compound of Formula (Ii)


11. The compound of claim 1 wherein R³ is an optionally substitutedbridged (C₅-C₁₂)cycloalkyl group, optionally substituted bridged (C₂-C₁₀)heterocyclyl group, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₆-C₁₀)aryl, optionally substituted(C₁-C₁₀)heteroaryl or optionally substituted (C₂-C ₁₀)heterocyclyl. 12.The compound of claim 11 wherein R³ is optionally substitutedcyclopropyl, optionally substituted cyclobutyl, optionally substitutedcyclopentyl, optionally substituted cyclohexyl, optionally substitutedphenyl, optionally substituted adamantanyl, optionally substitutedazetidinyl, optionally substituted bicyclo[2.1.1]hexyl, optionallysubstituted bicyclo[2.2.1]heptyl, optionally substitutedbicyclo[2.2.2]octyl, optionally substituted bicyclo[3.2.1]octyl,optionally substituted bicyclo[3.1.1]heptyl, optionally substitutedazabicyclo[3.2.1]octanyl, optionally substitutedazabicyclo[2.2.1]heptanyl, optionally substituted2-azabicyclo[3.2.1]octanyl, optionally substitutedazabicyclo[3.2.2]nonanyl, optionally substitutedbicyclo[2.2.1]hept-2-enyl, optionally substituted piperidinyl,optionally substituted pyrrolidinyl or optionally substitutedtetrahydrofuranyl.
 13. The compound of claim 1 wherein R³ is A-D-E-G andA is a bond, —C(O)—, optionally substituted (C₁-C₆)alkylene,—C(O)N(R^(a))—R^(e)—, —N(R^(a))C(O)—R^(e)—, —O—, —N(R^(a))—, —S—,—C(O—R^(a))(R^(b))—R^(e)—, —S(O)₂N(R^(a))—, —N(R^(a))S(O)₂— or—N(R^(a))C(O)N(R^(b))—.
 14. The compound of claim 13 wherein D is anoptionally substituted azetidinyl, optionally substitutedbicyclo[2.2.2]octanylene, optionally substitutedbicyclo[2.2.1]heptylene, optionally substituted bicyclo[2.1.1]hexylene,optionally substituted cyclobutylene, optionally substitutedcyclopentylene, optionally substituted cyclohexylene, optionallysubstituted bicyclo[2.2.1]hept-2-enylene, optionally substitutedpiperidinyl, or optionally substituted pyrrolidinyl.
 15. The compound ofclaim 14 wherein E is —R^(e)—C(O)—R^(e)—, R^(e)—O—R^(e),—R^(e)—S(O)₂—R^(e)—, —R^(e)—N(R^(a))—R^(e), —R^(e)—N(R^(a))C(O)—R^(e)—,13 R^(e)—C(O)N(R^(a))R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—, or—R^(e)—S(O)₂N(R^(a))R^(e)—.
 16. The compound of claim 15 wherein G is—OR^(a), —CN, —N(R^(a))S(O)₂R^(b), —S(O)₂N(R^(a))(R^(b)), optionallysubstituted (C₁-C₆)alkyl, optionally substituted cyclopropyl, optionallysubstituted cyclobutyl, optionally substituted cyclopentyl, optionallysubstituted phenyl, optionally substituted pyridazine, optionallysubstituted pyrazine, optionally substituted pyrimidine, optionallysubstituted pyrazole, optionally substituted pyrrolidine, optionallysubstituted quinazoline, optionally substituted pyridine, optionallysubstituted thiazolidine or optionally substituted triazole.
 17. Thecompound of claim 16 wherein A is a bond; D is optionally substitutedcyclopentylene, optionally substituted bicyclo[2.2.2]octanylene,optionally substituted azetidinyl, or optionally substitutedpiperidinyl; E is —R^(e)—C(O)—R^(e)—, —R^(e)—N(R^(a))—R^(e)—,—R^(e)—S(O)₂N(R^(a))—R^(e), —R^(e)—S(O)₂—R^(e)—, or—R^(e)—N(R^(a))S(O)₂—R^(e)—; wherein R^(e) for each occurrence isindependently a bond or an optionally substituted (C₁-C₆)alkylene; and Gis —CN, optionally substituted cyclopropyl, optionally substitutedcyclobutyl, optionally substituted cyclopentyl, optionally substitutedphenyl, optionally substituted pyrazine, optionally substitutedpyridazine, optionally substituted pyrazole, or optionally substitutedpyridine.
 18. The compound of claim 17 wherein R¹, R², R⁴, R⁵ and R⁶where present are each independently hydrogen or an optionallysubstituted —(C₁-C₄)alkyl.
 19. The compound of claim 18 wherein thecompound is a compound of Formula (Ia)


20. The compound of claim 18 wherein the compound is a compound ofFormula (Ib)


21. The compound of claim 18 wherein the compound is a compound ofFormula (Ic)


22. The compound of claim 19 wherein the compound is


23. The compound of claim 19 wherein the compound is


24. The compound of claim 19 wherein the compound is


25. The compound of claim 21 wherein A is a bond; D is optionallysubstituted cyclopentylene or optionally substituted piperidine; E is—R^(e)—N(R^(a))—R^(e)—, —R^(e)—S(O)₂ N(R^(a))—R^(e), —R^(e)—C(O)—R^(e),—R^(e)—S(O)₂—R^(e), or —R^(e)—N(R^(a))S(O)₂—R^(e)—; and G is —CN,optionally substituted phenyl, optionally substituted pyrazine,optionally substituted pyridazine, optionally substituted pyrazole, oroptionally substituted pyridine.
 26. The compound of claim 20 whereinthe compound is


27. The compound of claim 18 wherein G is optionally substituted phenyl,optionally substituted pyrazine, optionally substituted pyrazole,optionally substituted pyridazine or optionally substituted pyridine.28. The compound of claim 11 wherein R² and R⁵ are each independentlyhydrogen, deuterium, —N(R^(a))(R^(b)), halogen, —OR^(a), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —NO₂, —C(O)OR^(a), —CN, —C(O)N(R^(a))(R^(b)),—N(R^(a))C(O)(R^(b)), —C(O)R^(a), —C(OH)R^(a)R^(b),—N(R^(a))S(O)₂—R^(b), —S(O)₂N(R^(a))(R^(b)), —CF₃, —OCF₃, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₃-C₁₂)cycloalkyl,optionally substituted (C₆-C₁₀)aryl, optionally substituted(C₁-C₁₀)heteroaryl or optionally substituted (C₁-C₁₀)heterocyclyl. 29.The compound of claim 28 wherein R¹ is optionally substituted(C₆-C₁₀)aryl or optionally substituted (C₁-C₁₀)heteroaryl.
 30. Thecompound of claim 29 wherein R² is hydrogen, halogen, —CN,—C(O)NR^(a)R^(b), —CF₃, optionally substituted —(C₁-C₆)alkyl, optionallysubstituted —(C₃-C₆)cycloalkyl, optionally substituted benzo(b)thienyl,optionally substituted benzimidazolyl, optionally substitutedbenzofuranyl, optionally substituted benzoxazolyl, optionallysubstituted benzothiazolyl, optionally substituted benzothiadiazolyl,optionally substituted furanyl, optionally substituted imidazolyl,optionally substituted indolinyl, optionally substituted indolyl,optionally substituted indazolyl, optionally substituted isoxazolyl,optionally substituted isoindolinyl, optionally substituted morpholinyl,optionally substituted oxadiazolyl, optionally substituted phenyl,optionally substituted piperazinyl, optionally substituted piperidinyl,optionally substituted pyranyl, optionally substituted pyrazolyl,optionally substituted pyrazolo[3,4-d]pyrimidinyl, optionallysubstituted pyridinyl, optionally substituted pyrimidinyl, optionallysubstituted pyrrolidinyl, optionally substituted pyrrolyl, optionallysubstituted optionally pyrrolo[2,3-d]pyrimidinyl, substitutedquinolinyl, optionally substituted thiomorpholinyl, optionallysubstituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl,optionally substituted tetrahydroindolyl, optionally substitutedthiazolyl, or optionally substituted thienyl.
 31. The compound of claim30 wherein R¹ is optionally substituted azaindole, optionallysubstituted benzofuran, optionally substituted benzothiazole, optionallysubstituted benzoxazole, optionally substituted furan, optionallysubstituted imidazole, optionally substituted imidazoxazole, optionallysubstituted imidazopyrazine, optionally substituted imidazopyridine,optionally substituted indazole, optionally substituted indole,optionally substituted isoquinoline, optionally substituted isothiazole,optionally substituted isoxazole, optionally substituted oxadiazole,optionally substituted oxazole, optionally substituted pyrazole,optionally substituted pyridine, optionally substituted pyrimidine,optionally substituted pyrazolopyridine, optionally substituted pyrrole,optionally substituted quinoline, optionally substituted quinazoline,optionally substituted thiazole, or optionally substituted thiophene.32. The compound of claim 31 wherein R⁵ is hydrogen, halogen, —NH₂ or—N(R^(a))(R^(b)).
 33. The compound of claim 32 wherein T is CH, U is N,Y is N, and X is CR³ wherein R³ is optionally substituted(C₃-C₁₂)cycloalkyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl or optionally substituted(C₂-C₁₀)heterocyclyl.
 34. The compound of claim 32 wherein T is CH, U isN, Y is C and X is NR³ wherein R³ is optionally substituted(C₃-C₁₀)cycloalkyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl, or optionally substituted(C₂-C₁₀)heterocyclyl.
 35. The compound of claim 32 wherein T is N, U isN, Y is N and X is CR³ wherein R³ is optionally substituted(C₃-C₁₀)cycloalkyl, optionally substituted (C₆-C₁₀)aryl, optionallysubstituted (C₁-C₁₀)heteroaryl or optionally substituted(C₂-C₁₀)heterocyclyl.
 36. A pharmaceutical composition comprising acompound of claim 1, a pharmaceutically acceptable carrier and excipientand a second therapeutic agent.
 37. The compound of claim 2 wherein R³is optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl; or R³ is -A-D-E-G wherein A is abond; D is optionally substituted cycloalkylene, optionally substitutedbridged cycloalkylene or optionally substituted heterocyclylene; E is—R^(e)—N(R^(a))C(O)O—R^(e)—, —R^(e)—N(R^(a))S(O)₂—R^(e)—,—R^(e)—N(R^(a))C(O) —R^(e)—, —R^(e)—C(O)—R^(e)—, —R^(e)—N(R^(a)) —R^(e)—or —R^(e)—S(O)₂—R^(e)—; wherein R^(e) is independently a bond,optionally substituted cycloalkyl or optionally substituted heteroaryl;G is hydrogen, CN, optionally substituted alkyl, optionally substitutedaryl, optionally substituted cycloalkyl, optionally substitutedheteroaryl or optionally substituted heterocyclyl; R¹ is hydrogen; R² ishydrogen; and R⁵ is hydrogen.
 38. The compound of claim 37 wherein thecompound is1-(2-methylcyclohexyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;cis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanaminehydrochloride;cis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanamine;tert-butyl(1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate;N-(4-(6H-pyrrolo [2,3-e][1,2,4]triazolo [4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)-3-chlorobenzenesulfonamide;N-(((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methyl)-1-cyanocyclopropanecarboxamide;1-(tetrahydro-2H-pyran-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;N-((1S,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclobutanesulfonamide;N-((1R,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclobutanesulfonamide;(R)-1-(piperidin-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazinehydrochloride;1-(piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;N-(cis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexyl)-2-cyanoacetamide;(R)-3-(3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidin-1-yl)-3-oxopropanenitrile;N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)pyrrolidine-1-carboxamide;N-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide;6-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)nicotinonitrile;3-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidin-1-yl)-3-oxopropanenitrile;N-(cis-3-methyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclobutanesulfonamide;1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;N-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-N-methylcyclopropanesulfonamide;N-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)thiophene-2-sulfonamide;1-cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine;5-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile;or5-((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile.39. The compound of claim 3 wherein R¹ is hydrogen or optionallysubstituted heteroaryl; R² is hydrogen; R³ is optionally substitutedcycloalkyl, optionally substituted aryl, or optionally substitutedheterocyclyl; or R³ is -A-D-E-G wherein A is a bond; D is optionallysubstituted cycloalkyl, optionally substituted bridged cycloalkyl oroptionally substituted heterocyclyl; E is —R^(e)—C(O)—R^(e)—,—R^(e)—N(R^(a))S(O)₂—R^(e)—, or —R^(e)—C(O)—R^(e); wherein R^(e) isindependently a bond, optionally substituted alkyl or optionallysubstituted cycloalkyl; G is hydrogen, CN or optionally substitutedalkyl; and R⁵ is H.
 40. The compound of claim 39 wherein in the compoundis3-((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)-3-oxopropanenitrile;7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-phenyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine;N-(4-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide;(R)-1-(3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carbonyl)cyclopropanecarbonitrile;orN-((1R,3R,4S)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylcyclopentyl)cyclopropanesulfonamide.41. The compound of claim 4 wherein R¹ is hydrogen; R² is hydrogen; R³is -A-D-E-G wherein A is a bond; D is optionally substituted cycloalkylor optionally substituted heterocyclyl; E is —R^(e)— or—R^(e)—C(O)—R^(e)—; wherein R^(e) is independently a bond, optionallysubstituted alkyl or optionally substituted cycloalkyl; and G ishydrogen, CN or optionally substituted alkyl; R⁴ is hydrogen oroptionally substituted cycloalkyl; and R⁵ is hydrogen.
 42. The compoundof claim 41 wherein the compound is8-cyclohexyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine;(R)-1-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carbonyl)cyclopropanecarbonitrile;3-((3S,4S)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylpiperidin-1-yl)-3-oxopropanenitrile;or 3-((3R,4R)-3-(3H-imidazo [1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylpiperidin-1-yl)-3-oxopropanenitrile. 43.The compound of claim 6 wherein R¹ is hydrogen, optionally substitutedaryl or optionally substituted heteroaryl; R² is hydrogen; R³ isoptionally substituted cycloalkyl; R⁵ is hydrogen; and R⁶ is hydrogen.44. the compound of claim 8 wherein R¹ is hydrogen; R² is hydrogen; R³is optionally substituted cycloalkyl or optionally substitutedheterocyclyl; or R³ is -A-D-E-G wherein A is a bond; D is optionallysubstituted cycloalkyl or optionally substituted heterocyclyl; E is—R^(e)—, —R^(e)—N(R^(a))—R^(e)—, —R^(e)—S(O)₂—R^(e)— or—R^(e)—N(R^(a))C(O)—R^(e)—; wherein R^(e) is independently a bond,optionally substituted alkyl or optionally substituted heteroaryl; G isCF₃, CN, optionally substituted alkyl, optionally substituted aryl,optionally substituted cycloalkyl, or optionally substituted heteroaryl;R⁵ is H; and R⁶ is H or optionally substituted alkyl.
 45. The compoundof claim 44, wherein the compound is1-cyclohexyl-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine;1-(1-benzylpiperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine;1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine;1-(1-(cyclopropylsulfonyl)piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine;1-cyclobutyl-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine;1-(tetrahydro-2H-pyran-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine;1-(tetrahydro-2H-pyran-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine;6-((1S,3S)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile;or6-((1S,3R)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile.46. The pharmaceutical composition of claim 36, wherein the secondtherapeutical agent is a cytokine suppressive anti-inflammatory drug, anantibody to or antagonist of other human cytokines or growth factors, oran NSAID.
 47. The pharmaceutical composition of claim 36, wherein thesecond therapeutical agent is IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7,IL-8, IL-11, IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II,GM-CSF, FGF, PDGF, CTLA or their ligands.
 48. The pharmaceuticalcomposition of claim 36, wherein the second therapeutical agent isadalimumab, golimumab, certolizumab pegol (CDP870), tocilizumab, CDP571, soluble p55 or p75 TNF receptor, Lenercept, infliximab, etanercept,rituximab, natalizumab, daclizumab, efalizumab, intravenousimmunoglobulin, alemtuzumab, anti-IL-6 receptor antibody, antibody toCD40 ligand and CD80, anti-B7 family antibody, anti-PD-1 familyantibody, anti-cytokine antibody, fonotolizumab, anti-IFNg antibody,anti-receptor receptor antibody, antibody to B-cell surface molecule,IL-12 antibody, anti-CD20 antibody, p75TNFRIgG, sIL-1RI, sIL-1R11,sIL-6R, IL-1 TRAP, MRA, CTLA4-IgG, IL-18 BP, interferon-gamma,interferon-β1a, interferon-β1b, interferon α-n3, interferon-α,interferon β1A-IF, Peginterferon α 2b, antiinflammatory cytokines,interferon-β, α-immunokine NNSO3, AnergiX.MS, MBP-8298, pirfenidoneallotrap 1258 (RDP-1258), sTNF-R1, TGF-beta2, alefacept, orlymphostat-B.
 49. The pharmaceutical composition of claim 36, whereinthe second therapeutical agent is a TNFα converting enzyme inhibitor, anIL-1 inhibitor, an Interleukin 11 or IL-18 antagonist, an IL-12antagonist, a soluble IL-12 receptor, an IL-12 binding protein, anon-depleting anti-CD4 inhibitor, a phosphodiesterase inhibitor, anadensosine agonist, an antithrombotic agent, a complement inhibitor, anadrenergic agent, an IL-1β converting enzyme inhibitor, a T-cellsignalling kinase inhibitor, a metalloproteinase inhibitor, ananti-IL-12, an anti-IL15, a S1P1 agonist, a PKC family inhibitor, a Tcell signaling inhibitor, a tyrosine kinase inhibitor, a caspaseinhibitor, an inhibitor of caspase-1, a chemokine receptor antagonist, aVLA-4 antagonist, an interferon gamma antagonist, an IL-4 agonist, aCOX2 inhibitor, a cannabinoid agonist, an inhibitor of PDE4, or a purinesynthesis inhibitor.
 50. The pharmaceutical composition of claim 36,wherein the second therapeutical agent is FK506, rapamycin,mycophenolate mofetil, leflunomide, ibuprofen, corticosteroids,sulfasalazine, 6-mercaptopurines, celecoxib, hydroxychloroquine sulfate,rofecoxib, naproxen, valdecoxib, meloxicam, acetate, gold sodiumthiomalate, aspirin, triamcinolone acetonide, propoxyphenenapsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac,diclofenac sodium, oxaprozin, oxycodone HC1, hydrocodonebitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra,tramadol HC1, salsalate, sulindac, cyanocobalamin/fa/pyridoxine,acetaminophen, alendronate sodium, morphine sulfate, lidocainehydrochloride, indomethacin, glucosamine sulf/chondroitin, amitriptylineHC1, sulfadiazine, oxycodone HC1/acetaminophen, olopatadine HC1misoprostol, naproxen sodium, omeprazole, cyclophosphamide, VX-740,Roflumilast, IC-485, CDC-801, FTY720, Ruboxistaurin, AEB-071, Mesopram,methotrexate, budenoside, dexamethasone, 5-aminosalicylic acid,olsalazine, IL-1ra, mesalamine, prednisone, azathioprine,mercaptopurine, methylprednisolone sodium succinate, diphenoxylate/atropsulfate, loperamide hydrochloride, ciprofloxacin/dextrose-water,tetracycline hydrochloride, fluocinonide, metronidazole,thimerosal/boric acid, cholestyramine/sucrose, ciprofloxacinhydrochloride, hyoscyamine sulfate, meperidine hydrochloride, midazolamhydrochloride, promethazine hydrochloride, sodium phosphate,sulfamethoxazole/trimethoprim, polycarbophil, propoxyphene napsylate,hydrocortisone, multivitamins, balsalazide disodium, codeinephosphate/apap, colesevelam HC1, cyanocobalamin, folic acid,levofloxacin, methylprednisolone, cyclosporine, 4-aminopyridine,tizanidine, hyperbaric oxygen, cladribine, prednisolone, dronabinol,mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate,sinnabidol, ABR-215062, BBR-2778, calagualine, CPI-1189, liposomeencapsulated mitoxantrone, MNA-715, neurovax, talampanel, teriflunomide,tiplimotide, misoprostol, minocyclin, betamethasone diprop augmented,dimethylsulfoxide, ketoprofen, tolmetin sodium, calcipotriene,glucosamine sulfate, risedronate sodium, thioguanine,hydroxychloroquine, steroids, cytotoxics, or LJP
 394. 51. A method oftreating or ameliorating a disease or disorder in an individual in needthereof, comprising administering to the individual a compound of claim1, wherein the disease or disorder is rheumatoid arthritis (RA),psoriasis, juvenile rheumatoid arthritis (JRA), Crohn's disease,psoriatic arthritis, ankylosing spondylitis, or ulcerative colitis. 52.The method of claim 51, wherein disease or disorder is rheumatoidarthritis (RA).
 53. The method of claim 51, wherein disease or disorderis psoriasis.